Research ArticleEffect of Essential Oils from Ginger (Zingiber officinale)and Turmeric (Curcuma longa) Rhizomes onSome Inflammatory Biomarkers in Cadmium InducedNeurotoxicity in Rats

Ayodele Jacob Akinyemi 1 and Philip Adeyemi Adeniyi2

1Department of Chemical Sciences Biochemistry Unit Afe Babalola University Ado-Ekiti Nigeria2Cell Biology and Neurotoxicity Unit Department of Anatomy College of Medicine and Health Sciences Nigeria

Correspondence should be addressed to Ayodele Jacob Akinyemi ajakinyemi2010yahoocouk

Received 20 May 2018 Accepted 13 September 2018 Published 8 October 2018

Academic Editor William Valentine

Copyright copy 2018 Ayodele JacobAkinyemi andPhilipAdeyemiAdeniyiThis is an open access article distributed under theCreativeCommons Attribution License which permits unrestricted use distribution and reproduction in any medium provided theoriginal work is properly cited

Studies have revealed that anti-inflammatory agents could provide beneficial effect in lowering the incidenceprogression ofneurological diseases Hence this study sought to investigate the effect of essential oils from Nigeria ginger and turmeric rhizomeson some cytokines in cadmium induced neurotoxicity The result revealed that essential oil from ginger and turmeric rhizomesexerts anti-inflammatory effect by preventing alterations of some cytokinesinflammatory biomarkers (IL-6 IL-10 and TNF-Alpha)levels and inhibits both hippocampus and prefrontal cortex acetylcholinesterase (AChE) and adenosine deaminase (ADA) activities(important enzymes relevant in the managementprevention of neurodegenerative diseases) in Cd treated rats In conclusionessential oil from ginger and turmeric rhizomes exerts anti-inflammatory properties in Cd induced neurotoxicity The observedeffect could be due to the volatile compounds as revealed by GC-MS analysis

1 Introduction

Neuroinflammation simply referred to as inflammation of thenervous tissue is caused by a variety of assault to the brainranging from infection traumatic brain injury toxic metabo-lites or autoimmunity [1] Recently it has been reported tocontribute to the pathogenesis of neurodegenerative diseasessuch as Alzheimerrsquos disease Parkinsonrsquos disease and mul-tiple sclerosis [1] Neuroinflammatory processes have beenlinked to the activation of three common cytokines namelyinterleukin-6 (IL-6) interleukin-1 beta (IL-1120573) and tumornecrosis factor alpha (TNF-120572) in the CNS [1] Several heavymetals have been implicated in the role of neuroinflammationandAlzheimerrsquos disease (AD) via formation of neurofibrillarytangles and amyloid-beta plaques [2 3]

Cadmium (Cd) is well known for its neurotoxic potentialand constitutes a serious global environmental health chal-lenge [2] Human is exposed to Cd via different sources such

as primary metal industries production of certain batteriesintake of contaminated food or water and inhalation oftobacco smoke or polluted air [2] Studies have shownthat Cd can easily cross the blood brain barrier (BBB) aspecialized structure composed of astrocytes and endothelialcells inducing neuroinflammatory processes [2ndash4] It hasbeen reported by Ashok et al [2] that Cd build up in thehuman body can induced neurotoxicity due to its high blood-brain barrier permeability Neurological disorders such asmemory impairments and hyperactivity in children mayoccur during Cd exposure [5] Disturbances in neuroin-flammatory processes have been noticed by Ashok et al[2] after exposure to Cd According to Wang and Du [6]the probable mechanism by which Cd induces neurologicaldamage is via oxidative stress however the toxic effects ofCd are rather complex and still debated Other mechanismssuch as alterations in inflammatory processes and proteindamage in neuronal cells have been proposed [5] Hence

HindawiJournal of ToxicologyVolume 2018 Article ID 4109491 7 pageshttpsdoiorg10115520184109491

2 Journal of Toxicology

current research focuses on anti-inflammatory agents fromeither synthetic or food sources that can help alleviate heavymetal induced neurodegeneration

Ginger otherwise known as the root of Zingiber officinaleRoscoe is commonly used as spice and discovered to havediverse pharmacological activities such as anti-inflammationantitumor and antioxidant properties [7ndash9] According toOboh et al [10] extract of ginger rhizomes inhibits acetyl-cholinesterase activity (key regulatory enzyme involved inneurodegeneration) in vitro Furthermore volatile oil ofginger has been reported to influence both cell-mediatedimmune response and nonspecific proliferation of T lympho-cyte [11]

Turmeric (Curcuma longa Linn) is one of the mainspices belonging to the family of Zingiberaceae used asmedicine condiment and cosmetic worldwide and valued asa functional food because of its health promoting potentials[12] It is comprised of a group of three curcuminoidscurcumin (diferuloylmethane) demethoxycurcumin andbisdemethoxycurcumin as well as volatile oils (tumeroneatlantone and zingiberone) sugars proteins and resinsSeveral studies have shown that essential oil from turmerichas significant biological activities including antifungalinsect repellent antibacterial antimutagenic anticarcino-genic antioxidant anti-inflammatory and antinociceptiveproperties [13ndash15]

More recently there has been growing attention onnatural anti-inflammatory agents capable of reducing orpreventing neuroinflammation coupled with the fact thatthere are few pharmacological studies regarding the use ofessential oils from ginger and turmeric rhizomes in the man-agementprevention of neurodegenerative diseases Hencethe anti-inflammatory effect of essential oil from ginger andturmeric rhizomes in cadmium induced neurotoxicity in ratswas evaluated by assessing their effect on some cytokinesand hippocampus and prefrontal cortex acetylcholinesterase(AChE) and adenosine deaminase (ADA) activities (impor-tant enzymes relevant in the managementprevention ofneurodegenerative diseases)

2 Materials and Methods

21 Chemicals Cadmium chloride (CdCl2) was obtained

from Oxford Laboratory Mumbai India and solubilizedin normal saline Acetylthiocholine iodide adenosine 551015840-dithiobis 2-nitrobenzoic acid (DTNB) and Tris-HCl werepurchased from SigmandashAldrich St Louis MO USA Allother reagents used in this study were of analytical grade andthe water was glass distilled

22 Sample Collection and Extraction of Essential Oils FreshNigeria ginger (Zingiber officinale Roscoe) and turmeric(Curcuma longa Linn) rhizomes were purchased from thelocal market of Ado-Ekiti Nigeria The rhizomes wereidentified and a voucher specimen was deposited with theHerbarium at the Department of Plant science laboratoryFaculty of science Ekiti State University Ado-Ekiti Nigeria

Thereafter fresh ginger and turmeric rhizomes (100 gof each) were subjected to hydrodistillation in a Clevenger

apparatus for 3 h The obtained oils were dried over anhy-drous sodium sulfate The oils were stored at 4∘C in arefrigerator until used for experiment

23 Animals Adult male albino rats (twelve weeks old)were obtained from the animal breeding unit at College ofMedicine Afe Babalola University Nigeria The rats werekept under good ventilation and illumination condition andreceived standard diet and water ad libitum Animals werecared for according to US National Institute of Health (NIH)ethical guidelines Treatment protocol was in accordancewith the ethical requirement of the Animal Use and CareCommittee of Afe Babalola University Ado-Ekiti Nigeria

24 Experimental Design In the present study the Cd wasadministered according to Goncalves et al [16] while thechoice of the essential oil doses (50mgkg) was made basedon a preliminary acute toxicity study where we obtainedbeneficial results of this compound in brain of rats (Datanot shown) After acclimatization period sixty (60) rats weredivided randomly into six groups of ten (10) animals eachnamely

(i) Group I serves as the control and rats of this groupreceived daily administration of 03 DMSO (vehi-cle of essential oil) orally plus saline (1mLkg) viaintraperitoneally (ip)

(ii) Group II received daily injections of saline (1mLkg)ip plus essential oil from turmeric (50mgkg) orally

(iii) Group III received daily injections of saline (1mLkg)ip plus essential oil from ginger (50mgkg) orally

(iv) Group IV received daily administration of 03DMSO (vehicle of essential oil) orally plus Cd(25mgkg) ip

(v) Group V received daily administration of essential oilfrom turmeric (50mgkg) orally plus Cd (25mgkg)via ip

(vi) Group VI received daily administration of essentialoil from ginger (50mgkg) orally plus Cd (25mgkg)via ip

The experiment lasted for 14 days both Cd and essential oilwere administered daily Essential oil was prepared in DMSO(03) and administered orally 30min before Cd injectionAfter the last day of treatment (14th day) animals werefasted overnight and euthanized according to the approvedprotocol The whole brains as well as prefrontal cortex andhippocampus were isolated and homogenized in 100mMpotassium phosphate pH 75 The homogenates were cen-trifuged at 14000 times g for 10min at 4∘C and the supernatantwas used for the subsequent enzymatic assays

25 Quantification of Cytokine Levels Using ELISAmdashMarkerfor Inflammation Whole brain tissue cytokine (TNF-120572 IL-6 and IL-10) levels were determined by ELISA using Quan-tikine Immunoassay kits (RampD systems) according to themanufacturerrsquos instructions Briefly 96-well microplates were

Journal of Toxicology 3

sensitized with primary antibody at room temperature for30min Then the tissue sample was added and incubatedfor another 30min and wash After washing secondary anti-body conjugated with peroxidase was added and incubatedThereafter the cytokine concentration was measured usingan ELISA plate reader

26 Biomarkers for Neurotoxicity

261 Enzymatic Assay of Acetylcholinesterase (AChE) ActivityAChE activity was measured using a 96-well microplatereader based on Ellman et al [17] In the 96-well plates25120583L of tissue homogenate followed by 125120583L of 3mMDTNB and 25120583L of buffer was added The resultant mixturewas incubated at 30∘C for 15min Finally 25120583L of 15mMsubstrate solution was added and the absorbance was mea-sured at 405 nm every 30 s for 2mins using a MicroplateSpectrophotometer (Molecular Devices Sunnyvale CA)Absorbance was plotted against time and the enzyme activitywas calculated

262 Adenosine Deaminase (ADA) Activity Assay ADAactivity determination was performed as described by Guistiand Galanti [18] In brief 50 120583L of tissue homogenate fol-lowed by 50 120583L of 21mM of adenosine pH 65 was incubatedat 37∘C for 60min Absorbance was measured at 630 nmusing a Microplate Spectrophotometer (Molecular DevicesSunnyvale CA) Enzyme activity was calculated in units perliter (UL)

27 Gas Chromatography-Mass Spectrometry (GCMS) Anal-ysis The samples were analyzed for volatile compoundsusing 7820A gas chromatograph coupled to 5975C inert massspectrometer (with triple axis detector) with electron-impactsource (Agilent Technologies) The stationary phase of sepa-ration of the compounds was HP-5 capillary column coatedwith 5 Phenyl Methyl Siloxane (30m length x 032mmdiameter x 025120583m film thickness) (Agilent Technologies)The carrier gas was Helium (He) used at constant flow rateof 16mLmin at an initial nominal pressure of 284 psi andaverage velocity of 46 cmsec 1 120583L of the samples was injectedin split less mode at an injection temperature of 260∘CPurge flow was 215mLmin at 050min with a total flow of258mLmin gas saver mode was switched on Oven wasinitially programmed at 60∘C (1min) and then ramped at4∘Cmin to 110∘C (3min) then 8∘Cmin to 260∘C (5min)and 10∘Cmin to 300∘C (12min) Run time was 5625minwith a 3min solvent delay The mass spectrometer wasoperated in electron-impact ionization mode at 70 eV withion source temperature of 230∘C quadrupole temperature of150∘C and transfer line temperature of 280∘C

The identification of the compounds was achieved onthe basis of retention time Kovats Index literature reportedretention index using a homologous series of n-alkanes(C8ndashC25 hydrocarbons Polyscience Corp Niles IL) coin-jection with standards (Sigma Aldrich St Louis MO) andmass spectra library search (NIST Wiley and Nbs) and bycomparing with the mass spectral literature data

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil +

Cd0

20

40

60

lowastlowastlowast

lowastlowast

Groups

IL-1

0 Le

vel (

pgm

l)

Figure 1 Effect of essential oil from ginger (Zingiber officinale)and turmeric (Curcuma longa) on interleukin-10 (IL-10) level incadmium-induced neuroinflammation in rats Data represent themean plusmn SEM of a group of eight rats (lowastlowastP lt 001 lowastlowastlowastP lt 0001vs control P lt 001 P lt 0001 vs Cd Induced) Key Controlreceived normal saline + vehicle Tur Oil received normal saline +turmeric essential oil (50mgkg) Ging Oil received normal saline +ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) GingOil + Cd received Cd + ginger essential oil (50mgkg)

28 Total Protein Concentration Protein concentration wasdetermined according to themethod of Bradford (1976) usingalbumin as standard This was done to normalize the resultsobtained

29 Statistical Analysis All the results were represented asmean plusmn SEM performed in triplicate Statistical analysisused was software of GraphPad Prism 40 (GraphPad Soft-ware Inc San Diego CA) One-way analysis of variance(ANOVA) followed by Duncanrsquos multiple range tests wasused and probability of P lt 005 was considered to bestatistically significant

3 Results

31 Cytokine Biomarkers The effects of essential oil fromNigeria ginger and turmeric rhizomes on some cytokines[interleukin 1 (IL-10) interleukin 6 (IL-6) and tumor necro-sis factor alpha (TNF-120572)] level in cadmium treated rats areshown in Figures 1ndash3 Cadmium administration caused asignificant (P lt 005) reduction in IL-10 level with a con-comitant increase in IL-6 and TNF-120572 level when compared tocontrol However cotreatment with essential oil from gingerand turmeric rhizome alters the level of these cytokines bypreventing a decrease in IL-10 and causing a reduction in IL-6 and TNF-120572 levels when compared with Cd untreated group(Figures 1ndash3)

32 Acetylcholinesterase Activity Figure 4 represent the effectof essential oil from Nigeria ginger and turmeric rhizomeson hippocampus and pre-frontal cortex AChE activity incadmium treated rats (Figures 4(a) and 4(b)) We observed asignificant (P lt 005) inhibitory effect on both hippocampus

4 Journal of Toxicology

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80 lowastlowastlowast

lowastlowast

Groups

IL-6

Lev

el (p

gm

l)

Figure 2 Effect of essential oil from ginger (Zingiber officinale) andturmeric (Curcuma longa) on interleukin-6 (IL-6) level in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEMof a group of eight rats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control Plt 001 P lt 0001 vs Cd Induced) Key Control received normalsaline + vehicle Tur Oil received normal saline + turmeric essentialoil (50mgkg) Ging Oil received normal saline + ginger essentialoil (50mgkg) Cd Induced received Cd + vehicle Tur Oil + Cdreceived Cd + turmeric essential oil (50mgkg) Ging Oil + Cdreceived Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

50

100

150

200

lowastlowastlowast

lowastlowast

Groups

TNF-

Alp

ha L

evel

(pg

ml)

Figure 3 Effect of essential oil from ginger (Zingiber officinale)and turmeric (Curcuma longa) on Tumor necrosis factor alpha(TNF-120572) level in cadmium-induced neuroinflammation in ratsData represent the mean plusmn SEM of a group of eight rats (lowastlowastP lt 001lowastlowastlowastP lt 0001 vs Control P lt 001vs Cd Induced) Key Controlreceived normal saline + vehicle Tur Oil received normal saline +turmeric essential oil (50mgkg) Ging Oil received normal saline +ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) GingOil + Cd received Cd + ginger essential oil (50mgkg)

and prefrontal cortex AChE activity by the essential oils whencompared with Cd exposed group

33 Adenosine Deaminase Activity Furthermore cadmiumadministration caused a significant (P lt 005) increase inhippocampus and prefrontal cortex ADA activity whencompared to control However treatment with essential oilfrom ginger and turmeric rhizome respectively prevents an

increase in ADA activity when compared with Cd untreatedgroup (Figures 5(a) and 5(b))

34 GC-MS Analysis In order to justify the efficacy ofthe essential oils we characterized the oils for volatileoil components using gas chromatography analysis accord-ing to their retention indices (RI) on a HP-5MS columnand the observed results are listed in Table 1 The resultrevealed that the major essential oils from turmeric rhizomesare Eucalyptol (7646) 120572-Terpinene (441) 120574-Terpinene(332) p-Cymene (131) and 120572-Terpineol (062)while 120572-Zingiberene (1743) 120573-Sesquiphellandrene (310) Euca-lyptol (275) Furfaral (176) 120572-Terpineol (135) endo-Borneol (131) Limonene (121)Thunbergol (084) Cit-ral (056) Oxirane (045) Caryophyllene oxide (042)Nerolidol (031) exo-Norborneol (027) cis-Verbenol(012) Linaloloxide (006) and Squalene (002) are themajor essential oil compounds detected in ginger rhizomes

4 Discussion

The production of amyloid beta proteins by 120573-secretase(BACE) and 120574-secretase in frontal cortex and hippocampushas been linked to the pathogenesis of AD [2] Several studieshave established the relationship between neuroinflamma-tion and AD linking the involvement of heavy metals [2 319 20]

In the present study Cd administration caused a reduc-tion in IL-10 (anti-inflammatory cytokine) with a concomi-tant increase in IL-6 andTNF-120572 (pro-inflammatory cytokine)levels when compared to control Previous studies haveshown that Cd can induced neuroinflammatory pathology bymechanism involving blood-brain barrier leakage microgliaactivation and infiltration of immune cells into the brain [219 20] It is interesting to note that cotreatment with essentialoil from ginger and turmeric rhizomes prevents alteration inthe level of these cytokines (Figures 1ndash3)This is an indicationthat the essential oils exert immunomodulatory activityand offer neuroprotection against inflammatory processesassociated with neurodegeneration This activity could beattributed to the volatile compounds present (Table 1) thathave been extensively studied for their anti-inflammatoryproperties and their ability to inhibit inflammatory mediators[9 14 21 22]

It is well established that the brain interacts dynami-cally with the immune system to modulate inflammationthrough a neural pathway otherwise called cholinergic anti-inflammatory pathway [23] This pathway consists of thevagus nerve acetylcholine (ACh) and the 1205727 subunit of thenicotinic acetylcholine receptor [23] Studies have demon-strated that ACh a neurotransmitter attenuates the produc-tion of TNF IL-6 and IL-18 by human macrophages at theposttranscriptional stage and alter IL-10 release which indi-cates a direct inhibitory effect of ACh on proinflammatorycytokine production [23ndash26]

Acetylcholine (ACh) is rapidly hydrolyzed by acetyl-cholinesterase (AChE) in neural synapses [26] Consideringthe anti-inflammatory effect of ACh it is possible to suggestthat AChE activity is an intrinsic regulator of inflammation

Journal of Toxicology 5

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020lowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020

00025lowastlowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(b)

Figure 4 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)acetylcholinesterase (AChE) activity in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEM of a group of eight rats(lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil received normal saline+ turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

100lowastlowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

lowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(b)

Figure 5 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)adenosine deaminase (ADA) activity in cadmium-induced neuroinflammation in rats Data represent the mean plusmn SEM of a group of eightrats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 005 P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil receivednormal saline + turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced receivedCd + vehicle Tur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

In the present study treatment with essential oils from bothginger and turmeric rhizomes inhibited hippocampus andpre-frontal cortex AChE activity when compared with Cdexposed group (Figure 4) This result highlights the pivotalrole of acetylcholine in inflammation and provides efficacyof the essential oil from ginger and turmeric as acetyl-cholinesterase inhibitor for the treatment of AD associatedwith inflammatory response Previous studies have shownthat peritoneal injection of acetylcholinesterase inhibitorsreduces serum proinflammatory cytokine levels in brain andblood and decreases serum acetylcholinesterase activity inmice [27 28]

It is interesting to note that both acetylcholine (ACh) andadenosine triphosphate (ATP) are co-released from the samemotor nerve endings in the CNS and have been recognisedas an important neurotransmitters involved in the process

of neuroimmunomodulation [29ndash31] ATP acts as a fastexcitatory neurotransmitter and presynaptic neuromodulator[32] Its breakdown product adenosine plays an importantmodulatory role in neuronal activity and neuroprotectiveactions in pathological conditions [32 33] In the presentstudy adenosine deaminase (ADA) activity (an importantenzyme involves in the regulation of adenosine level) wasincreased in hippocampus and pre-frontal cortex of Cd-treated rats when compared to control However treatmentwith essential oil from ginger and turmeric rhizome respec-tively prevents an increase in ADA activity when comparedwith Cd treated group (Figure 5) This action may lead to anincreased extracellular adenosine level and offers neuropro-tection during inflammatory response

In conclusion this study documents that treatmentwith essential oil from ginger and turmeric rhizomes exert

6 Journal of Toxicology

Table 1 Chemical composition found in the essential oils from Nigeria ginger and turmeric rhizomes

Compound NameGinger Turmeric

Retention time (min) Percent total of compound() Retention time (min) Percent total of compound

()exo-Norborneol 3663 027 ndash ndashEucalyptol 5194 275 5200 7646Linaloloxide 6511 006 ndash ndashendo-Borneol 8589 131 ndash ndashFurfural 9135 176 ndash ndash120572-Terpineol 9343 135 9331 062Limonene 12625 121 ndash ndashp-Cymene ndash ndash 13061 131120574-Terpinene ndash ndash 14350 332Oxirane 18358 045 ndash ndashCitral 18869 056 ndash ndash120572-Terpinene ndash ndash 19151 441cis-Verbenol 23368 012 ndash ndashThunbergol 23961 084 ndash ndashSqualene 25220 002 ndash ndashCaryophyllene oxide 25504 042 ndash ndashNerolidol 28205 031 ndash ndash120572-Zingiberene 4308 174 ndash ndash120573-Sesquiphellandrene 4485 310 ndash ndashOther components ndash 100 ndash 100

immunomodulatory effect in Cd exposed rat The inhibitionof AChE and ADA activities by these oils could suggestpossible mechanism of action for their anti-inflammatoryproperties Hence essential oil from ginger and turmericrhizomes could be harnessed as anti-inflammatory supple-ments for the managementprevention of neurodegenerativediseases associated with inflammation

Data Availability

The rawprocessed data required to reproduce these findingsare available but cannot be shared at this time

Conflicts of Interest

The authors declare no conflicts of interest

Acknowledgments

The corresponding author is grateful to the World Academyof Sciences (TWAS) for financial support through the indi-vidual TWAS research Grant no FR3240293337 for timelycompletion of this research

References

[1] D J Allison and D S Ditor ldquoThe common inflammatoryetiology of depression and cognitive impairment a therapeutictargetrdquo Journal of Neuroinflammation vol 11 no 1 pp 151ndash1552014

[2] A Ashok N K Rai S Tripathi and S Bandyopadhyay ldquoExpo-sure to As- Cd- and Pb-mixture induces A120573 amyloidogenicAPP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young ratsrdquo ToxicologicalSciences vol 143 no 1 pp 64ndash80 2015

[3] A Justin-Thenmozhi M Dhivya Bharathi R Kiruthika TManivasagam A Borah and M M Essa ldquoAttenuation ofaluminum chloride-induced neuroinflammation and caspaseactivation through the AKTGSK-3120573 pathway by hesperidin inwistar ratsrdquo Neurotoxicity Research vol 34 no 8 pp 463ndash4762018

[4] M E Gerlofs-Nijland D van Berlo F R Cassee R P F SchinsK Wang and A Campbell ldquoEffect of prolonged exposure todiesel engine exhaust on proinflammatory markers in differentregions of the rat brainrdquoParticle and Fibre Toxicology vol 17 pp7ndash12 2010

[5] O H El-Habit and A E Abdel Moneim ldquoTesting the genotox-icity cytotoxicity and oxidative stress of cadmium and nickeland their additive effect in male micerdquo Biological Trace ElementResearch vol 159 no 1-3 pp 364ndash372 2014

[6] B Wang and Y Du ldquoCadmium and Its Neurotoxic EffectsrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID898034 12 pages 2013

[7] H Liu and Y Zhou ldquoEffect of alcohol extract of Zingiberofficinale rose on immunological function of mice with tumorrdquoJournal of Hygiene Research vol 31 pp 208-209 2002

[8] Y Masuda H Kikuzaki M Hisamoto and N NakatanildquoAntioxidant properties of gingerol related compounds fromgingerrdquo BioFactors vol 21 no 1ndash4 pp 293ndash296 2004

Journal of Toxicology 7

[9] H-L Zhou Y-M Deng and Q-M Xie ldquoThe modulatoryeffects of the volatile oil of ginger on the cellular immuneresponse in vitro and in vivo in micerdquo Journal of Ethnopharma-cology vol 105 no 1-2 pp 301ndash305 2006

[10] G Oboh A O Ademiluyi and A J Akinyemi ldquoInhibition ofacetylcholinesterase activities and some pro-oxidant inducedlipid peroxidation in rat brain by two varieties of ginger(Zingiber officinale)rdquo Experimental and Toxicologic Pathologyvol 64 no 4 pp 315ndash319 2012

[11] CWilasrusmee S Kittur J Siddiqui D Bruch SWilasrusmeeand D S Kittur ldquoIn vitro immunomodulatory effects of tencommonly used herbs on murine lymphocytesrdquo The Journal ofAlternative and Complementary Medicine vol 8 no 4 pp 467ndash475 2002

[12] G K Jayaprakasha L JM Rao andK K Sakariah ldquoChemistryand biological activities of Clongardquo Trends in Food Science ampTechnology vol 16 no 12 pp 533ndash548 2005

[13] K Hastak N Lubri S D Jakhi et al ldquoEffect of turmeric oil andturmeric oleoresin on cytogenetic damage in patients sufferingfrom oral submucous fibrosisrdquoCancer Letters vol 116 no 2 pp265ndash269 1997

[14] V B Liju K Jeena andR Kuttan ldquoAn evaluation of antioxidantanti-inflammatory and antinociceptive activities of essential oilfrom Curcuma longa Lrdquo Indian Journal of Pharmacology vol43 no 5 pp 526ndash531 2011

[15] K Norajit N Laohakunjit and O Kerdchoechuen ldquoAntibacte-rial effect of five Zingiberaceae essential oilsrdquoMolecules vol 12pp 2047ndash2060 2012

[16] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[17] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[18] G Guisti and B Galanti ldquoColorimetric methodrdquo in Methodsof Enzymatic Analysis H U Bergmeyer Ed pp 315-23 VerlagChemie Weinheim Germany 1984

[19] J T Rogers and D K Lahiri ldquoMetal and inflammatory targetsfor alzheimers diseaserdquo Current Drug Targets vol 5 no 6 pp535ndash551 2004

[20] J T Rogers V Venkataramani C Washburn et al ldquoA role foramyloid precursor protein translation to restore iron home-ostasis and ameliorate lead (Pb) neurotoxicityrdquo Journal ofNeurochemistry pp 479ndash494 2016

[21] J S Jurenka ldquoAnti-inflammatory properties of curcumin amajor constituent of Curcuma longa a review of preclinical andclinical researchrdquoAlternativeMedicine Review vol 14 no 2 pp141ndash153 2009

[22] A S Bagad J A Joseph N Bhaskaran and A Agarwal ldquoCom-parative evaluation of anti-inflammatory activity of curcum-inoids turmerones and aqueous extract of Curcuma longardquoAdvances in Pharmacological Sciences vol 2013 Article ID805756 7 pages 2013

[23] V A Pavlov W R Parrish M Rosas-Ballina et al ldquoBrainacetylcholinesterase activity controls systemic cytokine levelsthrough the cholinergic anti-inflammatory pathwayrdquo BrainBehavior and Immunity vol 23 no 1 pp 41ndash45 2009

[24] H Wang M Yu M Ochani et al ldquoNicotinic acetylcholinereceptor 1205727 subunit is an essential regulator of inflammationrdquoNature vol 421 no 6921 pp 384ndash388 2003

[25] R PAGaykema S-MParkCRMcKibbin andL EGoehlerldquoLipopolysaccharide suppresses activation of the tuberomam-millary histaminergic system concomitant with behavior Anovel target of immune-sensory pathwaysrdquo Neuroscience vol152 no 1 pp 273ndash287 2008

[26] M Rosas-Ballina and K J Tracey ldquoCholinergic control ofinflammationrdquo Journal of Internal Medicine vol 265 no 6 pp663ndash679 2009

[27] Y Pollak A Gilboa O Ben-Menachem T Ben-Hur H Soreqand R Yirmiya ldquoAcetylcholinesterase inhibitors reduce brainand blood interleukin-1120573 productionrdquoAnnals of Neurology vol57 no 5 pp 741ndash745 2005

[28] K Ofek K S Krabbe T Evron et al ldquoCholinergic statusmodulations in human volunteers under acute inflammationrdquoJournal ofMolecularMedicine vol 85 no 11 pp 1239ndash1251 2007

[29] T J Searl and E M Silinsky ldquoMechanisms of neuromodulationas dissected using Sr2+ at motor nerve endingsrdquo Journal ofNeurophysiology vol 99 no 6 pp 2779ndash2788 2008

[30] H Zimmermann ldquoATP and acetylcholine equal brethrenrdquoNeurochemistry International vol 52 no 4-5 pp 634ndash6482008

[31] G Burnstock ldquoP2X ion channel receptors and inflammationrdquoPurinergic Signalling vol 12 no 1 pp 59ndash67 2016

[32] G Burnstock ldquoPurinergic signalling and neurological diseasesAn updaterdquoCNS and Neurological Disorders - Drug Targets vol16 no 3 pp 257ndash265 2017

[33] D Rial D R Lara and R A Cunha ldquoThe adenosine neuro-modulation system in schizophreniardquo International Review ofNeurobiology vol 119 pp 395ndash449 2014

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

Journal of Toxicology 3

sensitized with primary antibody at room temperature for30min Then the tissue sample was added and incubatedfor another 30min and wash After washing secondary anti-body conjugated with peroxidase was added and incubatedThereafter the cytokine concentration was measured usingan ELISA plate reader

26 Biomarkers for Neurotoxicity

261 Enzymatic Assay of Acetylcholinesterase (AChE) ActivityAChE activity was measured using a 96-well microplatereader based on Ellman et al [17] In the 96-well plates25120583L of tissue homogenate followed by 125120583L of 3mMDTNB and 25120583L of buffer was added The resultant mixturewas incubated at 30∘C for 15min Finally 25120583L of 15mMsubstrate solution was added and the absorbance was mea-sured at 405 nm every 30 s for 2mins using a MicroplateSpectrophotometer (Molecular Devices Sunnyvale CA)Absorbance was plotted against time and the enzyme activitywas calculated

262 Adenosine Deaminase (ADA) Activity Assay ADAactivity determination was performed as described by Guistiand Galanti [18] In brief 50 120583L of tissue homogenate fol-lowed by 50 120583L of 21mM of adenosine pH 65 was incubatedat 37∘C for 60min Absorbance was measured at 630 nmusing a Microplate Spectrophotometer (Molecular DevicesSunnyvale CA) Enzyme activity was calculated in units perliter (UL)

27 Gas Chromatography-Mass Spectrometry (GCMS) Anal-ysis The samples were analyzed for volatile compoundsusing 7820A gas chromatograph coupled to 5975C inert massspectrometer (with triple axis detector) with electron-impactsource (Agilent Technologies) The stationary phase of sepa-ration of the compounds was HP-5 capillary column coatedwith 5 Phenyl Methyl Siloxane (30m length x 032mmdiameter x 025120583m film thickness) (Agilent Technologies)The carrier gas was Helium (He) used at constant flow rateof 16mLmin at an initial nominal pressure of 284 psi andaverage velocity of 46 cmsec 1 120583L of the samples was injectedin split less mode at an injection temperature of 260∘CPurge flow was 215mLmin at 050min with a total flow of258mLmin gas saver mode was switched on Oven wasinitially programmed at 60∘C (1min) and then ramped at4∘Cmin to 110∘C (3min) then 8∘Cmin to 260∘C (5min)and 10∘Cmin to 300∘C (12min) Run time was 5625minwith a 3min solvent delay The mass spectrometer wasoperated in electron-impact ionization mode at 70 eV withion source temperature of 230∘C quadrupole temperature of150∘C and transfer line temperature of 280∘C

The identification of the compounds was achieved onthe basis of retention time Kovats Index literature reportedretention index using a homologous series of n-alkanes(C8ndashC25 hydrocarbons Polyscience Corp Niles IL) coin-jection with standards (Sigma Aldrich St Louis MO) andmass spectra library search (NIST Wiley and Nbs) and bycomparing with the mass spectral literature data

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil +

Cd0

20

40

60

lowastlowastlowast

lowastlowast

Groups

IL-1

0 Le

vel (

pgm

l)

Figure 1 Effect of essential oil from ginger (Zingiber officinale)and turmeric (Curcuma longa) on interleukin-10 (IL-10) level incadmium-induced neuroinflammation in rats Data represent themean plusmn SEM of a group of eight rats (lowastlowastP lt 001 lowastlowastlowastP lt 0001vs control P lt 001 P lt 0001 vs Cd Induced) Key Controlreceived normal saline + vehicle Tur Oil received normal saline +turmeric essential oil (50mgkg) Ging Oil received normal saline +ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) GingOil + Cd received Cd + ginger essential oil (50mgkg)

28 Total Protein Concentration Protein concentration wasdetermined according to themethod of Bradford (1976) usingalbumin as standard This was done to normalize the resultsobtained

29 Statistical Analysis All the results were represented asmean plusmn SEM performed in triplicate Statistical analysisused was software of GraphPad Prism 40 (GraphPad Soft-ware Inc San Diego CA) One-way analysis of variance(ANOVA) followed by Duncanrsquos multiple range tests wasused and probability of P lt 005 was considered to bestatistically significant

3 Results

31 Cytokine Biomarkers The effects of essential oil fromNigeria ginger and turmeric rhizomes on some cytokines[interleukin 1 (IL-10) interleukin 6 (IL-6) and tumor necro-sis factor alpha (TNF-120572)] level in cadmium treated rats areshown in Figures 1ndash3 Cadmium administration caused asignificant (P lt 005) reduction in IL-10 level with a con-comitant increase in IL-6 and TNF-120572 level when compared tocontrol However cotreatment with essential oil from gingerand turmeric rhizome alters the level of these cytokines bypreventing a decrease in IL-10 and causing a reduction in IL-6 and TNF-120572 levels when compared with Cd untreated group(Figures 1ndash3)

32 Acetylcholinesterase Activity Figure 4 represent the effectof essential oil from Nigeria ginger and turmeric rhizomeson hippocampus and pre-frontal cortex AChE activity incadmium treated rats (Figures 4(a) and 4(b)) We observed asignificant (P lt 005) inhibitory effect on both hippocampus

4 Journal of Toxicology

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80 lowastlowastlowast

lowastlowast

Groups

IL-6

Lev

el (p

gm

l)

Figure 2 Effect of essential oil from ginger (Zingiber officinale) andturmeric (Curcuma longa) on interleukin-6 (IL-6) level in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEMof a group of eight rats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control Plt 001 P lt 0001 vs Cd Induced) Key Control received normalsaline + vehicle Tur Oil received normal saline + turmeric essentialoil (50mgkg) Ging Oil received normal saline + ginger essentialoil (50mgkg) Cd Induced received Cd + vehicle Tur Oil + Cdreceived Cd + turmeric essential oil (50mgkg) Ging Oil + Cdreceived Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

50

100

150

200

lowastlowastlowast

lowastlowast

Groups

TNF-

Alp

ha L

evel

(pg

ml)

Figure 3 Effect of essential oil from ginger (Zingiber officinale)and turmeric (Curcuma longa) on Tumor necrosis factor alpha(TNF-120572) level in cadmium-induced neuroinflammation in ratsData represent the mean plusmn SEM of a group of eight rats (lowastlowastP lt 001lowastlowastlowastP lt 0001 vs Control P lt 001vs Cd Induced) Key Controlreceived normal saline + vehicle Tur Oil received normal saline +turmeric essential oil (50mgkg) Ging Oil received normal saline +ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) GingOil + Cd received Cd + ginger essential oil (50mgkg)

and prefrontal cortex AChE activity by the essential oils whencompared with Cd exposed group

33 Adenosine Deaminase Activity Furthermore cadmiumadministration caused a significant (P lt 005) increase inhippocampus and prefrontal cortex ADA activity whencompared to control However treatment with essential oilfrom ginger and turmeric rhizome respectively prevents an

increase in ADA activity when compared with Cd untreatedgroup (Figures 5(a) and 5(b))

34 GC-MS Analysis In order to justify the efficacy ofthe essential oils we characterized the oils for volatileoil components using gas chromatography analysis accord-ing to their retention indices (RI) on a HP-5MS columnand the observed results are listed in Table 1 The resultrevealed that the major essential oils from turmeric rhizomesare Eucalyptol (7646) 120572-Terpinene (441) 120574-Terpinene(332) p-Cymene (131) and 120572-Terpineol (062)while 120572-Zingiberene (1743) 120573-Sesquiphellandrene (310) Euca-lyptol (275) Furfaral (176) 120572-Terpineol (135) endo-Borneol (131) Limonene (121)Thunbergol (084) Cit-ral (056) Oxirane (045) Caryophyllene oxide (042)Nerolidol (031) exo-Norborneol (027) cis-Verbenol(012) Linaloloxide (006) and Squalene (002) are themajor essential oil compounds detected in ginger rhizomes

4 Discussion

The production of amyloid beta proteins by 120573-secretase(BACE) and 120574-secretase in frontal cortex and hippocampushas been linked to the pathogenesis of AD [2] Several studieshave established the relationship between neuroinflamma-tion and AD linking the involvement of heavy metals [2 319 20]

In the present study Cd administration caused a reduc-tion in IL-10 (anti-inflammatory cytokine) with a concomi-tant increase in IL-6 andTNF-120572 (pro-inflammatory cytokine)levels when compared to control Previous studies haveshown that Cd can induced neuroinflammatory pathology bymechanism involving blood-brain barrier leakage microgliaactivation and infiltration of immune cells into the brain [219 20] It is interesting to note that cotreatment with essentialoil from ginger and turmeric rhizomes prevents alteration inthe level of these cytokines (Figures 1ndash3)This is an indicationthat the essential oils exert immunomodulatory activityand offer neuroprotection against inflammatory processesassociated with neurodegeneration This activity could beattributed to the volatile compounds present (Table 1) thathave been extensively studied for their anti-inflammatoryproperties and their ability to inhibit inflammatory mediators[9 14 21 22]

It is well established that the brain interacts dynami-cally with the immune system to modulate inflammationthrough a neural pathway otherwise called cholinergic anti-inflammatory pathway [23] This pathway consists of thevagus nerve acetylcholine (ACh) and the 1205727 subunit of thenicotinic acetylcholine receptor [23] Studies have demon-strated that ACh a neurotransmitter attenuates the produc-tion of TNF IL-6 and IL-18 by human macrophages at theposttranscriptional stage and alter IL-10 release which indi-cates a direct inhibitory effect of ACh on proinflammatorycytokine production [23ndash26]

Acetylcholine (ACh) is rapidly hydrolyzed by acetyl-cholinesterase (AChE) in neural synapses [26] Consideringthe anti-inflammatory effect of ACh it is possible to suggestthat AChE activity is an intrinsic regulator of inflammation

Journal of Toxicology 5

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020lowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020

00025lowastlowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(b)

Figure 4 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)acetylcholinesterase (AChE) activity in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEM of a group of eight rats(lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil received normal saline+ turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

100lowastlowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

lowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(b)

Figure 5 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)adenosine deaminase (ADA) activity in cadmium-induced neuroinflammation in rats Data represent the mean plusmn SEM of a group of eightrats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 005 P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil receivednormal saline + turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced receivedCd + vehicle Tur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

In the present study treatment with essential oils from bothginger and turmeric rhizomes inhibited hippocampus andpre-frontal cortex AChE activity when compared with Cdexposed group (Figure 4) This result highlights the pivotalrole of acetylcholine in inflammation and provides efficacyof the essential oil from ginger and turmeric as acetyl-cholinesterase inhibitor for the treatment of AD associatedwith inflammatory response Previous studies have shownthat peritoneal injection of acetylcholinesterase inhibitorsreduces serum proinflammatory cytokine levels in brain andblood and decreases serum acetylcholinesterase activity inmice [27 28]

It is interesting to note that both acetylcholine (ACh) andadenosine triphosphate (ATP) are co-released from the samemotor nerve endings in the CNS and have been recognisedas an important neurotransmitters involved in the process

of neuroimmunomodulation [29ndash31] ATP acts as a fastexcitatory neurotransmitter and presynaptic neuromodulator[32] Its breakdown product adenosine plays an importantmodulatory role in neuronal activity and neuroprotectiveactions in pathological conditions [32 33] In the presentstudy adenosine deaminase (ADA) activity (an importantenzyme involves in the regulation of adenosine level) wasincreased in hippocampus and pre-frontal cortex of Cd-treated rats when compared to control However treatmentwith essential oil from ginger and turmeric rhizome respec-tively prevents an increase in ADA activity when comparedwith Cd treated group (Figure 5) This action may lead to anincreased extracellular adenosine level and offers neuropro-tection during inflammatory response

In conclusion this study documents that treatmentwith essential oil from ginger and turmeric rhizomes exert

6 Journal of Toxicology

Table 1 Chemical composition found in the essential oils from Nigeria ginger and turmeric rhizomes

Compound NameGinger Turmeric

Retention time (min) Percent total of compound() Retention time (min) Percent total of compound

()exo-Norborneol 3663 027 ndash ndashEucalyptol 5194 275 5200 7646Linaloloxide 6511 006 ndash ndashendo-Borneol 8589 131 ndash ndashFurfural 9135 176 ndash ndash120572-Terpineol 9343 135 9331 062Limonene 12625 121 ndash ndashp-Cymene ndash ndash 13061 131120574-Terpinene ndash ndash 14350 332Oxirane 18358 045 ndash ndashCitral 18869 056 ndash ndash120572-Terpinene ndash ndash 19151 441cis-Verbenol 23368 012 ndash ndashThunbergol 23961 084 ndash ndashSqualene 25220 002 ndash ndashCaryophyllene oxide 25504 042 ndash ndashNerolidol 28205 031 ndash ndash120572-Zingiberene 4308 174 ndash ndash120573-Sesquiphellandrene 4485 310 ndash ndashOther components ndash 100 ndash 100

immunomodulatory effect in Cd exposed rat The inhibitionof AChE and ADA activities by these oils could suggestpossible mechanism of action for their anti-inflammatoryproperties Hence essential oil from ginger and turmericrhizomes could be harnessed as anti-inflammatory supple-ments for the managementprevention of neurodegenerativediseases associated with inflammation

Data Availability

The rawprocessed data required to reproduce these findingsare available but cannot be shared at this time

Conflicts of Interest

The authors declare no conflicts of interest

Acknowledgments

The corresponding author is grateful to the World Academyof Sciences (TWAS) for financial support through the indi-vidual TWAS research Grant no FR3240293337 for timelycompletion of this research

References

[1] D J Allison and D S Ditor ldquoThe common inflammatoryetiology of depression and cognitive impairment a therapeutictargetrdquo Journal of Neuroinflammation vol 11 no 1 pp 151ndash1552014

[2] A Ashok N K Rai S Tripathi and S Bandyopadhyay ldquoExpo-sure to As- Cd- and Pb-mixture induces A120573 amyloidogenicAPP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young ratsrdquo ToxicologicalSciences vol 143 no 1 pp 64ndash80 2015

[3] A Justin-Thenmozhi M Dhivya Bharathi R Kiruthika TManivasagam A Borah and M M Essa ldquoAttenuation ofaluminum chloride-induced neuroinflammation and caspaseactivation through the AKTGSK-3120573 pathway by hesperidin inwistar ratsrdquo Neurotoxicity Research vol 34 no 8 pp 463ndash4762018

[4] M E Gerlofs-Nijland D van Berlo F R Cassee R P F SchinsK Wang and A Campbell ldquoEffect of prolonged exposure todiesel engine exhaust on proinflammatory markers in differentregions of the rat brainrdquoParticle and Fibre Toxicology vol 17 pp7ndash12 2010

[5] O H El-Habit and A E Abdel Moneim ldquoTesting the genotox-icity cytotoxicity and oxidative stress of cadmium and nickeland their additive effect in male micerdquo Biological Trace ElementResearch vol 159 no 1-3 pp 364ndash372 2014

[6] B Wang and Y Du ldquoCadmium and Its Neurotoxic EffectsrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID898034 12 pages 2013

[7] H Liu and Y Zhou ldquoEffect of alcohol extract of Zingiberofficinale rose on immunological function of mice with tumorrdquoJournal of Hygiene Research vol 31 pp 208-209 2002

[8] Y Masuda H Kikuzaki M Hisamoto and N NakatanildquoAntioxidant properties of gingerol related compounds fromgingerrdquo BioFactors vol 21 no 1ndash4 pp 293ndash296 2004

Journal of Toxicology 7

[9] H-L Zhou Y-M Deng and Q-M Xie ldquoThe modulatoryeffects of the volatile oil of ginger on the cellular immuneresponse in vitro and in vivo in micerdquo Journal of Ethnopharma-cology vol 105 no 1-2 pp 301ndash305 2006

[10] G Oboh A O Ademiluyi and A J Akinyemi ldquoInhibition ofacetylcholinesterase activities and some pro-oxidant inducedlipid peroxidation in rat brain by two varieties of ginger(Zingiber officinale)rdquo Experimental and Toxicologic Pathologyvol 64 no 4 pp 315ndash319 2012

[11] CWilasrusmee S Kittur J Siddiqui D Bruch SWilasrusmeeand D S Kittur ldquoIn vitro immunomodulatory effects of tencommonly used herbs on murine lymphocytesrdquo The Journal ofAlternative and Complementary Medicine vol 8 no 4 pp 467ndash475 2002

[12] G K Jayaprakasha L JM Rao andK K Sakariah ldquoChemistryand biological activities of Clongardquo Trends in Food Science ampTechnology vol 16 no 12 pp 533ndash548 2005

[13] K Hastak N Lubri S D Jakhi et al ldquoEffect of turmeric oil andturmeric oleoresin on cytogenetic damage in patients sufferingfrom oral submucous fibrosisrdquoCancer Letters vol 116 no 2 pp265ndash269 1997

[14] V B Liju K Jeena andR Kuttan ldquoAn evaluation of antioxidantanti-inflammatory and antinociceptive activities of essential oilfrom Curcuma longa Lrdquo Indian Journal of Pharmacology vol43 no 5 pp 526ndash531 2011

[15] K Norajit N Laohakunjit and O Kerdchoechuen ldquoAntibacte-rial effect of five Zingiberaceae essential oilsrdquoMolecules vol 12pp 2047ndash2060 2012

[16] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[17] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[18] G Guisti and B Galanti ldquoColorimetric methodrdquo in Methodsof Enzymatic Analysis H U Bergmeyer Ed pp 315-23 VerlagChemie Weinheim Germany 1984

[19] J T Rogers and D K Lahiri ldquoMetal and inflammatory targetsfor alzheimers diseaserdquo Current Drug Targets vol 5 no 6 pp535ndash551 2004

[20] J T Rogers V Venkataramani C Washburn et al ldquoA role foramyloid precursor protein translation to restore iron home-ostasis and ameliorate lead (Pb) neurotoxicityrdquo Journal ofNeurochemistry pp 479ndash494 2016

[21] J S Jurenka ldquoAnti-inflammatory properties of curcumin amajor constituent of Curcuma longa a review of preclinical andclinical researchrdquoAlternativeMedicine Review vol 14 no 2 pp141ndash153 2009

[22] A S Bagad J A Joseph N Bhaskaran and A Agarwal ldquoCom-parative evaluation of anti-inflammatory activity of curcum-inoids turmerones and aqueous extract of Curcuma longardquoAdvances in Pharmacological Sciences vol 2013 Article ID805756 7 pages 2013

[23] V A Pavlov W R Parrish M Rosas-Ballina et al ldquoBrainacetylcholinesterase activity controls systemic cytokine levelsthrough the cholinergic anti-inflammatory pathwayrdquo BrainBehavior and Immunity vol 23 no 1 pp 41ndash45 2009

[24] H Wang M Yu M Ochani et al ldquoNicotinic acetylcholinereceptor 1205727 subunit is an essential regulator of inflammationrdquoNature vol 421 no 6921 pp 384ndash388 2003

[25] R PAGaykema S-MParkCRMcKibbin andL EGoehlerldquoLipopolysaccharide suppresses activation of the tuberomam-millary histaminergic system concomitant with behavior Anovel target of immune-sensory pathwaysrdquo Neuroscience vol152 no 1 pp 273ndash287 2008

[26] M Rosas-Ballina and K J Tracey ldquoCholinergic control ofinflammationrdquo Journal of Internal Medicine vol 265 no 6 pp663ndash679 2009

[27] Y Pollak A Gilboa O Ben-Menachem T Ben-Hur H Soreqand R Yirmiya ldquoAcetylcholinesterase inhibitors reduce brainand blood interleukin-1120573 productionrdquoAnnals of Neurology vol57 no 5 pp 741ndash745 2005

[28] K Ofek K S Krabbe T Evron et al ldquoCholinergic statusmodulations in human volunteers under acute inflammationrdquoJournal ofMolecularMedicine vol 85 no 11 pp 1239ndash1251 2007

[29] T J Searl and E M Silinsky ldquoMechanisms of neuromodulationas dissected using Sr2+ at motor nerve endingsrdquo Journal ofNeurophysiology vol 99 no 6 pp 2779ndash2788 2008

[30] H Zimmermann ldquoATP and acetylcholine equal brethrenrdquoNeurochemistry International vol 52 no 4-5 pp 634ndash6482008

[31] G Burnstock ldquoP2X ion channel receptors and inflammationrdquoPurinergic Signalling vol 12 no 1 pp 59ndash67 2016

[32] G Burnstock ldquoPurinergic signalling and neurological diseasesAn updaterdquoCNS and Neurological Disorders - Drug Targets vol16 no 3 pp 257ndash265 2017

[33] D Rial D R Lara and R A Cunha ldquoThe adenosine neuro-modulation system in schizophreniardquo International Review ofNeurobiology vol 119 pp 395ndash449 2014

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

4 Journal of Toxicology

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80 lowastlowastlowast

lowastlowast

Groups

IL-6

Lev

el (p

gm

l)

Figure 2 Effect of essential oil from ginger (Zingiber officinale) andturmeric (Curcuma longa) on interleukin-6 (IL-6) level in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEMof a group of eight rats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control Plt 001 P lt 0001 vs Cd Induced) Key Control received normalsaline + vehicle Tur Oil received normal saline + turmeric essentialoil (50mgkg) Ging Oil received normal saline + ginger essentialoil (50mgkg) Cd Induced received Cd + vehicle Tur Oil + Cdreceived Cd + turmeric essential oil (50mgkg) Ging Oil + Cdreceived Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

50

100

150

200

lowastlowastlowast

lowastlowast

Groups

TNF-

Alp

ha L

evel

(pg

ml)

Figure 3 Effect of essential oil from ginger (Zingiber officinale)and turmeric (Curcuma longa) on Tumor necrosis factor alpha(TNF-120572) level in cadmium-induced neuroinflammation in ratsData represent the mean plusmn SEM of a group of eight rats (lowastlowastP lt 001lowastlowastlowastP lt 0001 vs Control P lt 001vs Cd Induced) Key Controlreceived normal saline + vehicle Tur Oil received normal saline +turmeric essential oil (50mgkg) Ging Oil received normal saline +ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) GingOil + Cd received Cd + ginger essential oil (50mgkg)

and prefrontal cortex AChE activity by the essential oils whencompared with Cd exposed group

33 Adenosine Deaminase Activity Furthermore cadmiumadministration caused a significant (P lt 005) increase inhippocampus and prefrontal cortex ADA activity whencompared to control However treatment with essential oilfrom ginger and turmeric rhizome respectively prevents an

increase in ADA activity when compared with Cd untreatedgroup (Figures 5(a) and 5(b))

34 GC-MS Analysis In order to justify the efficacy ofthe essential oils we characterized the oils for volatileoil components using gas chromatography analysis accord-ing to their retention indices (RI) on a HP-5MS columnand the observed results are listed in Table 1 The resultrevealed that the major essential oils from turmeric rhizomesare Eucalyptol (7646) 120572-Terpinene (441) 120574-Terpinene(332) p-Cymene (131) and 120572-Terpineol (062)while 120572-Zingiberene (1743) 120573-Sesquiphellandrene (310) Euca-lyptol (275) Furfaral (176) 120572-Terpineol (135) endo-Borneol (131) Limonene (121)Thunbergol (084) Cit-ral (056) Oxirane (045) Caryophyllene oxide (042)Nerolidol (031) exo-Norborneol (027) cis-Verbenol(012) Linaloloxide (006) and Squalene (002) are themajor essential oil compounds detected in ginger rhizomes

4 Discussion

The production of amyloid beta proteins by 120573-secretase(BACE) and 120574-secretase in frontal cortex and hippocampushas been linked to the pathogenesis of AD [2] Several studieshave established the relationship between neuroinflamma-tion and AD linking the involvement of heavy metals [2 319 20]

In the present study Cd administration caused a reduc-tion in IL-10 (anti-inflammatory cytokine) with a concomi-tant increase in IL-6 andTNF-120572 (pro-inflammatory cytokine)levels when compared to control Previous studies haveshown that Cd can induced neuroinflammatory pathology bymechanism involving blood-brain barrier leakage microgliaactivation and infiltration of immune cells into the brain [219 20] It is interesting to note that cotreatment with essentialoil from ginger and turmeric rhizomes prevents alteration inthe level of these cytokines (Figures 1ndash3)This is an indicationthat the essential oils exert immunomodulatory activityand offer neuroprotection against inflammatory processesassociated with neurodegeneration This activity could beattributed to the volatile compounds present (Table 1) thathave been extensively studied for their anti-inflammatoryproperties and their ability to inhibit inflammatory mediators[9 14 21 22]

It is well established that the brain interacts dynami-cally with the immune system to modulate inflammationthrough a neural pathway otherwise called cholinergic anti-inflammatory pathway [23] This pathway consists of thevagus nerve acetylcholine (ACh) and the 1205727 subunit of thenicotinic acetylcholine receptor [23] Studies have demon-strated that ACh a neurotransmitter attenuates the produc-tion of TNF IL-6 and IL-18 by human macrophages at theposttranscriptional stage and alter IL-10 release which indi-cates a direct inhibitory effect of ACh on proinflammatorycytokine production [23ndash26]

Acetylcholine (ACh) is rapidly hydrolyzed by acetyl-cholinesterase (AChE) in neural synapses [26] Consideringthe anti-inflammatory effect of ACh it is possible to suggestthat AChE activity is an intrinsic regulator of inflammation

Journal of Toxicology 5

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020lowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020

00025lowastlowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(b)

Figure 4 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)acetylcholinesterase (AChE) activity in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEM of a group of eight rats(lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil received normal saline+ turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

100lowastlowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

lowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(b)

Figure 5 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)adenosine deaminase (ADA) activity in cadmium-induced neuroinflammation in rats Data represent the mean plusmn SEM of a group of eightrats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 005 P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil receivednormal saline + turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced receivedCd + vehicle Tur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

In the present study treatment with essential oils from bothginger and turmeric rhizomes inhibited hippocampus andpre-frontal cortex AChE activity when compared with Cdexposed group (Figure 4) This result highlights the pivotalrole of acetylcholine in inflammation and provides efficacyof the essential oil from ginger and turmeric as acetyl-cholinesterase inhibitor for the treatment of AD associatedwith inflammatory response Previous studies have shownthat peritoneal injection of acetylcholinesterase inhibitorsreduces serum proinflammatory cytokine levels in brain andblood and decreases serum acetylcholinesterase activity inmice [27 28]

It is interesting to note that both acetylcholine (ACh) andadenosine triphosphate (ATP) are co-released from the samemotor nerve endings in the CNS and have been recognisedas an important neurotransmitters involved in the process

of neuroimmunomodulation [29ndash31] ATP acts as a fastexcitatory neurotransmitter and presynaptic neuromodulator[32] Its breakdown product adenosine plays an importantmodulatory role in neuronal activity and neuroprotectiveactions in pathological conditions [32 33] In the presentstudy adenosine deaminase (ADA) activity (an importantenzyme involves in the regulation of adenosine level) wasincreased in hippocampus and pre-frontal cortex of Cd-treated rats when compared to control However treatmentwith essential oil from ginger and turmeric rhizome respec-tively prevents an increase in ADA activity when comparedwith Cd treated group (Figure 5) This action may lead to anincreased extracellular adenosine level and offers neuropro-tection during inflammatory response

In conclusion this study documents that treatmentwith essential oil from ginger and turmeric rhizomes exert

6 Journal of Toxicology

Table 1 Chemical composition found in the essential oils from Nigeria ginger and turmeric rhizomes

Compound NameGinger Turmeric

Retention time (min) Percent total of compound() Retention time (min) Percent total of compound

()exo-Norborneol 3663 027 ndash ndashEucalyptol 5194 275 5200 7646Linaloloxide 6511 006 ndash ndashendo-Borneol 8589 131 ndash ndashFurfural 9135 176 ndash ndash120572-Terpineol 9343 135 9331 062Limonene 12625 121 ndash ndashp-Cymene ndash ndash 13061 131120574-Terpinene ndash ndash 14350 332Oxirane 18358 045 ndash ndashCitral 18869 056 ndash ndash120572-Terpinene ndash ndash 19151 441cis-Verbenol 23368 012 ndash ndashThunbergol 23961 084 ndash ndashSqualene 25220 002 ndash ndashCaryophyllene oxide 25504 042 ndash ndashNerolidol 28205 031 ndash ndash120572-Zingiberene 4308 174 ndash ndash120573-Sesquiphellandrene 4485 310 ndash ndashOther components ndash 100 ndash 100

immunomodulatory effect in Cd exposed rat The inhibitionof AChE and ADA activities by these oils could suggestpossible mechanism of action for their anti-inflammatoryproperties Hence essential oil from ginger and turmericrhizomes could be harnessed as anti-inflammatory supple-ments for the managementprevention of neurodegenerativediseases associated with inflammation

Data Availability

The rawprocessed data required to reproduce these findingsare available but cannot be shared at this time

Conflicts of Interest

The authors declare no conflicts of interest

Acknowledgments

The corresponding author is grateful to the World Academyof Sciences (TWAS) for financial support through the indi-vidual TWAS research Grant no FR3240293337 for timelycompletion of this research

References

[1] D J Allison and D S Ditor ldquoThe common inflammatoryetiology of depression and cognitive impairment a therapeutictargetrdquo Journal of Neuroinflammation vol 11 no 1 pp 151ndash1552014

[2] A Ashok N K Rai S Tripathi and S Bandyopadhyay ldquoExpo-sure to As- Cd- and Pb-mixture induces A120573 amyloidogenicAPP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young ratsrdquo ToxicologicalSciences vol 143 no 1 pp 64ndash80 2015

[3] A Justin-Thenmozhi M Dhivya Bharathi R Kiruthika TManivasagam A Borah and M M Essa ldquoAttenuation ofaluminum chloride-induced neuroinflammation and caspaseactivation through the AKTGSK-3120573 pathway by hesperidin inwistar ratsrdquo Neurotoxicity Research vol 34 no 8 pp 463ndash4762018

[4] M E Gerlofs-Nijland D van Berlo F R Cassee R P F SchinsK Wang and A Campbell ldquoEffect of prolonged exposure todiesel engine exhaust on proinflammatory markers in differentregions of the rat brainrdquoParticle and Fibre Toxicology vol 17 pp7ndash12 2010

[5] O H El-Habit and A E Abdel Moneim ldquoTesting the genotox-icity cytotoxicity and oxidative stress of cadmium and nickeland their additive effect in male micerdquo Biological Trace ElementResearch vol 159 no 1-3 pp 364ndash372 2014

[6] B Wang and Y Du ldquoCadmium and Its Neurotoxic EffectsrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID898034 12 pages 2013

[7] H Liu and Y Zhou ldquoEffect of alcohol extract of Zingiberofficinale rose on immunological function of mice with tumorrdquoJournal of Hygiene Research vol 31 pp 208-209 2002

[8] Y Masuda H Kikuzaki M Hisamoto and N NakatanildquoAntioxidant properties of gingerol related compounds fromgingerrdquo BioFactors vol 21 no 1ndash4 pp 293ndash296 2004

Journal of Toxicology 7

[9] H-L Zhou Y-M Deng and Q-M Xie ldquoThe modulatoryeffects of the volatile oil of ginger on the cellular immuneresponse in vitro and in vivo in micerdquo Journal of Ethnopharma-cology vol 105 no 1-2 pp 301ndash305 2006

[10] G Oboh A O Ademiluyi and A J Akinyemi ldquoInhibition ofacetylcholinesterase activities and some pro-oxidant inducedlipid peroxidation in rat brain by two varieties of ginger(Zingiber officinale)rdquo Experimental and Toxicologic Pathologyvol 64 no 4 pp 315ndash319 2012

[11] CWilasrusmee S Kittur J Siddiqui D Bruch SWilasrusmeeand D S Kittur ldquoIn vitro immunomodulatory effects of tencommonly used herbs on murine lymphocytesrdquo The Journal ofAlternative and Complementary Medicine vol 8 no 4 pp 467ndash475 2002

[12] G K Jayaprakasha L JM Rao andK K Sakariah ldquoChemistryand biological activities of Clongardquo Trends in Food Science ampTechnology vol 16 no 12 pp 533ndash548 2005

[13] K Hastak N Lubri S D Jakhi et al ldquoEffect of turmeric oil andturmeric oleoresin on cytogenetic damage in patients sufferingfrom oral submucous fibrosisrdquoCancer Letters vol 116 no 2 pp265ndash269 1997

[14] V B Liju K Jeena andR Kuttan ldquoAn evaluation of antioxidantanti-inflammatory and antinociceptive activities of essential oilfrom Curcuma longa Lrdquo Indian Journal of Pharmacology vol43 no 5 pp 526ndash531 2011

[15] K Norajit N Laohakunjit and O Kerdchoechuen ldquoAntibacte-rial effect of five Zingiberaceae essential oilsrdquoMolecules vol 12pp 2047ndash2060 2012

[16] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[17] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[18] G Guisti and B Galanti ldquoColorimetric methodrdquo in Methodsof Enzymatic Analysis H U Bergmeyer Ed pp 315-23 VerlagChemie Weinheim Germany 1984

[19] J T Rogers and D K Lahiri ldquoMetal and inflammatory targetsfor alzheimers diseaserdquo Current Drug Targets vol 5 no 6 pp535ndash551 2004

[20] J T Rogers V Venkataramani C Washburn et al ldquoA role foramyloid precursor protein translation to restore iron home-ostasis and ameliorate lead (Pb) neurotoxicityrdquo Journal ofNeurochemistry pp 479ndash494 2016

[21] J S Jurenka ldquoAnti-inflammatory properties of curcumin amajor constituent of Curcuma longa a review of preclinical andclinical researchrdquoAlternativeMedicine Review vol 14 no 2 pp141ndash153 2009

[22] A S Bagad J A Joseph N Bhaskaran and A Agarwal ldquoCom-parative evaluation of anti-inflammatory activity of curcum-inoids turmerones and aqueous extract of Curcuma longardquoAdvances in Pharmacological Sciences vol 2013 Article ID805756 7 pages 2013

[23] V A Pavlov W R Parrish M Rosas-Ballina et al ldquoBrainacetylcholinesterase activity controls systemic cytokine levelsthrough the cholinergic anti-inflammatory pathwayrdquo BrainBehavior and Immunity vol 23 no 1 pp 41ndash45 2009

[24] H Wang M Yu M Ochani et al ldquoNicotinic acetylcholinereceptor 1205727 subunit is an essential regulator of inflammationrdquoNature vol 421 no 6921 pp 384ndash388 2003

[25] R PAGaykema S-MParkCRMcKibbin andL EGoehlerldquoLipopolysaccharide suppresses activation of the tuberomam-millary histaminergic system concomitant with behavior Anovel target of immune-sensory pathwaysrdquo Neuroscience vol152 no 1 pp 273ndash287 2008

[26] M Rosas-Ballina and K J Tracey ldquoCholinergic control ofinflammationrdquo Journal of Internal Medicine vol 265 no 6 pp663ndash679 2009

[27] Y Pollak A Gilboa O Ben-Menachem T Ben-Hur H Soreqand R Yirmiya ldquoAcetylcholinesterase inhibitors reduce brainand blood interleukin-1120573 productionrdquoAnnals of Neurology vol57 no 5 pp 741ndash745 2005

[28] K Ofek K S Krabbe T Evron et al ldquoCholinergic statusmodulations in human volunteers under acute inflammationrdquoJournal ofMolecularMedicine vol 85 no 11 pp 1239ndash1251 2007

[29] T J Searl and E M Silinsky ldquoMechanisms of neuromodulationas dissected using Sr2+ at motor nerve endingsrdquo Journal ofNeurophysiology vol 99 no 6 pp 2779ndash2788 2008

[30] H Zimmermann ldquoATP and acetylcholine equal brethrenrdquoNeurochemistry International vol 52 no 4-5 pp 634ndash6482008

[31] G Burnstock ldquoP2X ion channel receptors and inflammationrdquoPurinergic Signalling vol 12 no 1 pp 59ndash67 2016

[32] G Burnstock ldquoPurinergic signalling and neurological diseasesAn updaterdquoCNS and Neurological Disorders - Drug Targets vol16 no 3 pp 257ndash265 2017

[33] D Rial D R Lara and R A Cunha ldquoThe adenosine neuro-modulation system in schizophreniardquo International Review ofNeurobiology vol 119 pp 395ndash449 2014

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

Journal of Toxicology 5

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020lowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

00000

00005

00010

00015

00020

00025lowastlowastlowast

Groups

AChE

act

ivity

(microm

ol A

ChE

min

mg

prot

ein)

(b)

Figure 4 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)acetylcholinesterase (AChE) activity in cadmium-induced neuroinflammation in rats Data represent themean plusmn SEM of a group of eight rats(lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil received normal saline+ turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced received Cd + vehicleTur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

100lowastlowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(a)

Control

Tur Oil

Ging Oil

Cd Induced

Tur Oil +

Cd

Ging Oil + Cd

0

20

40

60

80

lowast

Groups

Ade

nosin

e dea

min

ase a

ctiv

ity(U

L)

(b)

Figure 5 Effect of essential oil from ginger (Zingiber officinale) and turmeric (Curcuma longa) on prefrontal-cortex (a) and hippocampus (b)adenosine deaminase (ADA) activity in cadmium-induced neuroinflammation in rats Data represent the mean plusmn SEM of a group of eightrats (lowastlowastP lt 001 lowastlowastlowastP lt 0001 vs control P lt 005 P lt 001vs Cd Induced) Key Control received normal saline + vehicle Tur Oil receivednormal saline + turmeric essential oil (50mgkg) Ging Oil received normal saline + ginger essential oil (50mgkg) Cd Induced receivedCd + vehicle Tur Oil + Cd received Cd + turmeric essential oil (50mgkg) Ging Oil + Cd received Cd + ginger essential oil (50mgkg)

In the present study treatment with essential oils from bothginger and turmeric rhizomes inhibited hippocampus andpre-frontal cortex AChE activity when compared with Cdexposed group (Figure 4) This result highlights the pivotalrole of acetylcholine in inflammation and provides efficacyof the essential oil from ginger and turmeric as acetyl-cholinesterase inhibitor for the treatment of AD associatedwith inflammatory response Previous studies have shownthat peritoneal injection of acetylcholinesterase inhibitorsreduces serum proinflammatory cytokine levels in brain andblood and decreases serum acetylcholinesterase activity inmice [27 28]

It is interesting to note that both acetylcholine (ACh) andadenosine triphosphate (ATP) are co-released from the samemotor nerve endings in the CNS and have been recognisedas an important neurotransmitters involved in the process

of neuroimmunomodulation [29ndash31] ATP acts as a fastexcitatory neurotransmitter and presynaptic neuromodulator[32] Its breakdown product adenosine plays an importantmodulatory role in neuronal activity and neuroprotectiveactions in pathological conditions [32 33] In the presentstudy adenosine deaminase (ADA) activity (an importantenzyme involves in the regulation of adenosine level) wasincreased in hippocampus and pre-frontal cortex of Cd-treated rats when compared to control However treatmentwith essential oil from ginger and turmeric rhizome respec-tively prevents an increase in ADA activity when comparedwith Cd treated group (Figure 5) This action may lead to anincreased extracellular adenosine level and offers neuropro-tection during inflammatory response

In conclusion this study documents that treatmentwith essential oil from ginger and turmeric rhizomes exert

6 Journal of Toxicology

Table 1 Chemical composition found in the essential oils from Nigeria ginger and turmeric rhizomes

Compound NameGinger Turmeric

Retention time (min) Percent total of compound() Retention time (min) Percent total of compound

()exo-Norborneol 3663 027 ndash ndashEucalyptol 5194 275 5200 7646Linaloloxide 6511 006 ndash ndashendo-Borneol 8589 131 ndash ndashFurfural 9135 176 ndash ndash120572-Terpineol 9343 135 9331 062Limonene 12625 121 ndash ndashp-Cymene ndash ndash 13061 131120574-Terpinene ndash ndash 14350 332Oxirane 18358 045 ndash ndashCitral 18869 056 ndash ndash120572-Terpinene ndash ndash 19151 441cis-Verbenol 23368 012 ndash ndashThunbergol 23961 084 ndash ndashSqualene 25220 002 ndash ndashCaryophyllene oxide 25504 042 ndash ndashNerolidol 28205 031 ndash ndash120572-Zingiberene 4308 174 ndash ndash120573-Sesquiphellandrene 4485 310 ndash ndashOther components ndash 100 ndash 100

immunomodulatory effect in Cd exposed rat The inhibitionof AChE and ADA activities by these oils could suggestpossible mechanism of action for their anti-inflammatoryproperties Hence essential oil from ginger and turmericrhizomes could be harnessed as anti-inflammatory supple-ments for the managementprevention of neurodegenerativediseases associated with inflammation

Data Availability

The rawprocessed data required to reproduce these findingsare available but cannot be shared at this time

Conflicts of Interest

The authors declare no conflicts of interest

Acknowledgments

The corresponding author is grateful to the World Academyof Sciences (TWAS) for financial support through the indi-vidual TWAS research Grant no FR3240293337 for timelycompletion of this research

References

[1] D J Allison and D S Ditor ldquoThe common inflammatoryetiology of depression and cognitive impairment a therapeutictargetrdquo Journal of Neuroinflammation vol 11 no 1 pp 151ndash1552014

[2] A Ashok N K Rai S Tripathi and S Bandyopadhyay ldquoExpo-sure to As- Cd- and Pb-mixture induces A120573 amyloidogenicAPP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young ratsrdquo ToxicologicalSciences vol 143 no 1 pp 64ndash80 2015

[3] A Justin-Thenmozhi M Dhivya Bharathi R Kiruthika TManivasagam A Borah and M M Essa ldquoAttenuation ofaluminum chloride-induced neuroinflammation and caspaseactivation through the AKTGSK-3120573 pathway by hesperidin inwistar ratsrdquo Neurotoxicity Research vol 34 no 8 pp 463ndash4762018

[4] M E Gerlofs-Nijland D van Berlo F R Cassee R P F SchinsK Wang and A Campbell ldquoEffect of prolonged exposure todiesel engine exhaust on proinflammatory markers in differentregions of the rat brainrdquoParticle and Fibre Toxicology vol 17 pp7ndash12 2010

[5] O H El-Habit and A E Abdel Moneim ldquoTesting the genotox-icity cytotoxicity and oxidative stress of cadmium and nickeland their additive effect in male micerdquo Biological Trace ElementResearch vol 159 no 1-3 pp 364ndash372 2014

[6] B Wang and Y Du ldquoCadmium and Its Neurotoxic EffectsrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID898034 12 pages 2013

[7] H Liu and Y Zhou ldquoEffect of alcohol extract of Zingiberofficinale rose on immunological function of mice with tumorrdquoJournal of Hygiene Research vol 31 pp 208-209 2002

[8] Y Masuda H Kikuzaki M Hisamoto and N NakatanildquoAntioxidant properties of gingerol related compounds fromgingerrdquo BioFactors vol 21 no 1ndash4 pp 293ndash296 2004

Journal of Toxicology 7

[9] H-L Zhou Y-M Deng and Q-M Xie ldquoThe modulatoryeffects of the volatile oil of ginger on the cellular immuneresponse in vitro and in vivo in micerdquo Journal of Ethnopharma-cology vol 105 no 1-2 pp 301ndash305 2006

[10] G Oboh A O Ademiluyi and A J Akinyemi ldquoInhibition ofacetylcholinesterase activities and some pro-oxidant inducedlipid peroxidation in rat brain by two varieties of ginger(Zingiber officinale)rdquo Experimental and Toxicologic Pathologyvol 64 no 4 pp 315ndash319 2012

[11] CWilasrusmee S Kittur J Siddiqui D Bruch SWilasrusmeeand D S Kittur ldquoIn vitro immunomodulatory effects of tencommonly used herbs on murine lymphocytesrdquo The Journal ofAlternative and Complementary Medicine vol 8 no 4 pp 467ndash475 2002

[12] G K Jayaprakasha L JM Rao andK K Sakariah ldquoChemistryand biological activities of Clongardquo Trends in Food Science ampTechnology vol 16 no 12 pp 533ndash548 2005

[13] K Hastak N Lubri S D Jakhi et al ldquoEffect of turmeric oil andturmeric oleoresin on cytogenetic damage in patients sufferingfrom oral submucous fibrosisrdquoCancer Letters vol 116 no 2 pp265ndash269 1997

[14] V B Liju K Jeena andR Kuttan ldquoAn evaluation of antioxidantanti-inflammatory and antinociceptive activities of essential oilfrom Curcuma longa Lrdquo Indian Journal of Pharmacology vol43 no 5 pp 526ndash531 2011

[15] K Norajit N Laohakunjit and O Kerdchoechuen ldquoAntibacte-rial effect of five Zingiberaceae essential oilsrdquoMolecules vol 12pp 2047ndash2060 2012

[16] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[17] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[18] G Guisti and B Galanti ldquoColorimetric methodrdquo in Methodsof Enzymatic Analysis H U Bergmeyer Ed pp 315-23 VerlagChemie Weinheim Germany 1984

[19] J T Rogers and D K Lahiri ldquoMetal and inflammatory targetsfor alzheimers diseaserdquo Current Drug Targets vol 5 no 6 pp535ndash551 2004

[20] J T Rogers V Venkataramani C Washburn et al ldquoA role foramyloid precursor protein translation to restore iron home-ostasis and ameliorate lead (Pb) neurotoxicityrdquo Journal ofNeurochemistry pp 479ndash494 2016

[21] J S Jurenka ldquoAnti-inflammatory properties of curcumin amajor constituent of Curcuma longa a review of preclinical andclinical researchrdquoAlternativeMedicine Review vol 14 no 2 pp141ndash153 2009

[22] A S Bagad J A Joseph N Bhaskaran and A Agarwal ldquoCom-parative evaluation of anti-inflammatory activity of curcum-inoids turmerones and aqueous extract of Curcuma longardquoAdvances in Pharmacological Sciences vol 2013 Article ID805756 7 pages 2013

[23] V A Pavlov W R Parrish M Rosas-Ballina et al ldquoBrainacetylcholinesterase activity controls systemic cytokine levelsthrough the cholinergic anti-inflammatory pathwayrdquo BrainBehavior and Immunity vol 23 no 1 pp 41ndash45 2009

[24] H Wang M Yu M Ochani et al ldquoNicotinic acetylcholinereceptor 1205727 subunit is an essential regulator of inflammationrdquoNature vol 421 no 6921 pp 384ndash388 2003

[25] R PAGaykema S-MParkCRMcKibbin andL EGoehlerldquoLipopolysaccharide suppresses activation of the tuberomam-millary histaminergic system concomitant with behavior Anovel target of immune-sensory pathwaysrdquo Neuroscience vol152 no 1 pp 273ndash287 2008

[26] M Rosas-Ballina and K J Tracey ldquoCholinergic control ofinflammationrdquo Journal of Internal Medicine vol 265 no 6 pp663ndash679 2009

[27] Y Pollak A Gilboa O Ben-Menachem T Ben-Hur H Soreqand R Yirmiya ldquoAcetylcholinesterase inhibitors reduce brainand blood interleukin-1120573 productionrdquoAnnals of Neurology vol57 no 5 pp 741ndash745 2005

[28] K Ofek K S Krabbe T Evron et al ldquoCholinergic statusmodulations in human volunteers under acute inflammationrdquoJournal ofMolecularMedicine vol 85 no 11 pp 1239ndash1251 2007

[29] T J Searl and E M Silinsky ldquoMechanisms of neuromodulationas dissected using Sr2+ at motor nerve endingsrdquo Journal ofNeurophysiology vol 99 no 6 pp 2779ndash2788 2008

[30] H Zimmermann ldquoATP and acetylcholine equal brethrenrdquoNeurochemistry International vol 52 no 4-5 pp 634ndash6482008

[31] G Burnstock ldquoP2X ion channel receptors and inflammationrdquoPurinergic Signalling vol 12 no 1 pp 59ndash67 2016

[32] G Burnstock ldquoPurinergic signalling and neurological diseasesAn updaterdquoCNS and Neurological Disorders - Drug Targets vol16 no 3 pp 257ndash265 2017

[33] D Rial D R Lara and R A Cunha ldquoThe adenosine neuro-modulation system in schizophreniardquo International Review ofNeurobiology vol 119 pp 395ndash449 2014

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

6 Journal of Toxicology

Table 1 Chemical composition found in the essential oils from Nigeria ginger and turmeric rhizomes

Compound NameGinger Turmeric

Retention time (min) Percent total of compound() Retention time (min) Percent total of compound

()exo-Norborneol 3663 027 ndash ndashEucalyptol 5194 275 5200 7646Linaloloxide 6511 006 ndash ndashendo-Borneol 8589 131 ndash ndashFurfural 9135 176 ndash ndash120572-Terpineol 9343 135 9331 062Limonene 12625 121 ndash ndashp-Cymene ndash ndash 13061 131120574-Terpinene ndash ndash 14350 332Oxirane 18358 045 ndash ndashCitral 18869 056 ndash ndash120572-Terpinene ndash ndash 19151 441cis-Verbenol 23368 012 ndash ndashThunbergol 23961 084 ndash ndashSqualene 25220 002 ndash ndashCaryophyllene oxide 25504 042 ndash ndashNerolidol 28205 031 ndash ndash120572-Zingiberene 4308 174 ndash ndash120573-Sesquiphellandrene 4485 310 ndash ndashOther components ndash 100 ndash 100

immunomodulatory effect in Cd exposed rat The inhibitionof AChE and ADA activities by these oils could suggestpossible mechanism of action for their anti-inflammatoryproperties Hence essential oil from ginger and turmericrhizomes could be harnessed as anti-inflammatory supple-ments for the managementprevention of neurodegenerativediseases associated with inflammation

Data Availability

The rawprocessed data required to reproduce these findingsare available but cannot be shared at this time

Conflicts of Interest

The authors declare no conflicts of interest

Acknowledgments

The corresponding author is grateful to the World Academyof Sciences (TWAS) for financial support through the indi-vidual TWAS research Grant no FR3240293337 for timelycompletion of this research

References

[1] D J Allison and D S Ditor ldquoThe common inflammatoryetiology of depression and cognitive impairment a therapeutictargetrdquo Journal of Neuroinflammation vol 11 no 1 pp 151ndash1552014

[2] A Ashok N K Rai S Tripathi and S Bandyopadhyay ldquoExpo-sure to As- Cd- and Pb-mixture induces A120573 amyloidogenicAPP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young ratsrdquo ToxicologicalSciences vol 143 no 1 pp 64ndash80 2015

[3] A Justin-Thenmozhi M Dhivya Bharathi R Kiruthika TManivasagam A Borah and M M Essa ldquoAttenuation ofaluminum chloride-induced neuroinflammation and caspaseactivation through the AKTGSK-3120573 pathway by hesperidin inwistar ratsrdquo Neurotoxicity Research vol 34 no 8 pp 463ndash4762018

[4] M E Gerlofs-Nijland D van Berlo F R Cassee R P F SchinsK Wang and A Campbell ldquoEffect of prolonged exposure todiesel engine exhaust on proinflammatory markers in differentregions of the rat brainrdquoParticle and Fibre Toxicology vol 17 pp7ndash12 2010

[5] O H El-Habit and A E Abdel Moneim ldquoTesting the genotox-icity cytotoxicity and oxidative stress of cadmium and nickeland their additive effect in male micerdquo Biological Trace ElementResearch vol 159 no 1-3 pp 364ndash372 2014

[6] B Wang and Y Du ldquoCadmium and Its Neurotoxic EffectsrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID898034 12 pages 2013

[7] H Liu and Y Zhou ldquoEffect of alcohol extract of Zingiberofficinale rose on immunological function of mice with tumorrdquoJournal of Hygiene Research vol 31 pp 208-209 2002

[8] Y Masuda H Kikuzaki M Hisamoto and N NakatanildquoAntioxidant properties of gingerol related compounds fromgingerrdquo BioFactors vol 21 no 1ndash4 pp 293ndash296 2004

Journal of Toxicology 7

[9] H-L Zhou Y-M Deng and Q-M Xie ldquoThe modulatoryeffects of the volatile oil of ginger on the cellular immuneresponse in vitro and in vivo in micerdquo Journal of Ethnopharma-cology vol 105 no 1-2 pp 301ndash305 2006

[10] G Oboh A O Ademiluyi and A J Akinyemi ldquoInhibition ofacetylcholinesterase activities and some pro-oxidant inducedlipid peroxidation in rat brain by two varieties of ginger(Zingiber officinale)rdquo Experimental and Toxicologic Pathologyvol 64 no 4 pp 315ndash319 2012

[11] CWilasrusmee S Kittur J Siddiqui D Bruch SWilasrusmeeand D S Kittur ldquoIn vitro immunomodulatory effects of tencommonly used herbs on murine lymphocytesrdquo The Journal ofAlternative and Complementary Medicine vol 8 no 4 pp 467ndash475 2002

[12] G K Jayaprakasha L JM Rao andK K Sakariah ldquoChemistryand biological activities of Clongardquo Trends in Food Science ampTechnology vol 16 no 12 pp 533ndash548 2005

[13] K Hastak N Lubri S D Jakhi et al ldquoEffect of turmeric oil andturmeric oleoresin on cytogenetic damage in patients sufferingfrom oral submucous fibrosisrdquoCancer Letters vol 116 no 2 pp265ndash269 1997

[14] V B Liju K Jeena andR Kuttan ldquoAn evaluation of antioxidantanti-inflammatory and antinociceptive activities of essential oilfrom Curcuma longa Lrdquo Indian Journal of Pharmacology vol43 no 5 pp 526ndash531 2011

[15] K Norajit N Laohakunjit and O Kerdchoechuen ldquoAntibacte-rial effect of five Zingiberaceae essential oilsrdquoMolecules vol 12pp 2047ndash2060 2012

[16] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[17] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[18] G Guisti and B Galanti ldquoColorimetric methodrdquo in Methodsof Enzymatic Analysis H U Bergmeyer Ed pp 315-23 VerlagChemie Weinheim Germany 1984

[19] J T Rogers and D K Lahiri ldquoMetal and inflammatory targetsfor alzheimers diseaserdquo Current Drug Targets vol 5 no 6 pp535ndash551 2004

[20] J T Rogers V Venkataramani C Washburn et al ldquoA role foramyloid precursor protein translation to restore iron home-ostasis and ameliorate lead (Pb) neurotoxicityrdquo Journal ofNeurochemistry pp 479ndash494 2016

[21] J S Jurenka ldquoAnti-inflammatory properties of curcumin amajor constituent of Curcuma longa a review of preclinical andclinical researchrdquoAlternativeMedicine Review vol 14 no 2 pp141ndash153 2009

[22] A S Bagad J A Joseph N Bhaskaran and A Agarwal ldquoCom-parative evaluation of anti-inflammatory activity of curcum-inoids turmerones and aqueous extract of Curcuma longardquoAdvances in Pharmacological Sciences vol 2013 Article ID805756 7 pages 2013

[23] V A Pavlov W R Parrish M Rosas-Ballina et al ldquoBrainacetylcholinesterase activity controls systemic cytokine levelsthrough the cholinergic anti-inflammatory pathwayrdquo BrainBehavior and Immunity vol 23 no 1 pp 41ndash45 2009

[24] H Wang M Yu M Ochani et al ldquoNicotinic acetylcholinereceptor 1205727 subunit is an essential regulator of inflammationrdquoNature vol 421 no 6921 pp 384ndash388 2003

[25] R PAGaykema S-MParkCRMcKibbin andL EGoehlerldquoLipopolysaccharide suppresses activation of the tuberomam-millary histaminergic system concomitant with behavior Anovel target of immune-sensory pathwaysrdquo Neuroscience vol152 no 1 pp 273ndash287 2008

[26] M Rosas-Ballina and K J Tracey ldquoCholinergic control ofinflammationrdquo Journal of Internal Medicine vol 265 no 6 pp663ndash679 2009

[27] Y Pollak A Gilboa O Ben-Menachem T Ben-Hur H Soreqand R Yirmiya ldquoAcetylcholinesterase inhibitors reduce brainand blood interleukin-1120573 productionrdquoAnnals of Neurology vol57 no 5 pp 741ndash745 2005

[28] K Ofek K S Krabbe T Evron et al ldquoCholinergic statusmodulations in human volunteers under acute inflammationrdquoJournal ofMolecularMedicine vol 85 no 11 pp 1239ndash1251 2007

[29] T J Searl and E M Silinsky ldquoMechanisms of neuromodulationas dissected using Sr2+ at motor nerve endingsrdquo Journal ofNeurophysiology vol 99 no 6 pp 2779ndash2788 2008

[30] H Zimmermann ldquoATP and acetylcholine equal brethrenrdquoNeurochemistry International vol 52 no 4-5 pp 634ndash6482008

[31] G Burnstock ldquoP2X ion channel receptors and inflammationrdquoPurinergic Signalling vol 12 no 1 pp 59ndash67 2016

[32] G Burnstock ldquoPurinergic signalling and neurological diseasesAn updaterdquoCNS and Neurological Disorders - Drug Targets vol16 no 3 pp 257ndash265 2017

[33] D Rial D R Lara and R A Cunha ldquoThe adenosine neuro-modulation system in schizophreniardquo International Review ofNeurobiology vol 119 pp 395ndash449 2014

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

Journal of Toxicology 7

[9] H-L Zhou Y-M Deng and Q-M Xie ldquoThe modulatoryeffects of the volatile oil of ginger on the cellular immuneresponse in vitro and in vivo in micerdquo Journal of Ethnopharma-cology vol 105 no 1-2 pp 301ndash305 2006

[10] G Oboh A O Ademiluyi and A J Akinyemi ldquoInhibition ofacetylcholinesterase activities and some pro-oxidant inducedlipid peroxidation in rat brain by two varieties of ginger(Zingiber officinale)rdquo Experimental and Toxicologic Pathologyvol 64 no 4 pp 315ndash319 2012

[11] CWilasrusmee S Kittur J Siddiqui D Bruch SWilasrusmeeand D S Kittur ldquoIn vitro immunomodulatory effects of tencommonly used herbs on murine lymphocytesrdquo The Journal ofAlternative and Complementary Medicine vol 8 no 4 pp 467ndash475 2002

[12] G K Jayaprakasha L JM Rao andK K Sakariah ldquoChemistryand biological activities of Clongardquo Trends in Food Science ampTechnology vol 16 no 12 pp 533ndash548 2005

[13] K Hastak N Lubri S D Jakhi et al ldquoEffect of turmeric oil andturmeric oleoresin on cytogenetic damage in patients sufferingfrom oral submucous fibrosisrdquoCancer Letters vol 116 no 2 pp265ndash269 1997

[14] V B Liju K Jeena andR Kuttan ldquoAn evaluation of antioxidantanti-inflammatory and antinociceptive activities of essential oilfrom Curcuma longa Lrdquo Indian Journal of Pharmacology vol43 no 5 pp 526ndash531 2011

[15] K Norajit N Laohakunjit and O Kerdchoechuen ldquoAntibacte-rial effect of five Zingiberaceae essential oilsrdquoMolecules vol 12pp 2047ndash2060 2012

[16] J F Goncalves F T Nicoloso P da Costa et al ldquoBehaviorand brain enzymatic changes after long-term intoxication withcadmium salt or contaminated potatoesrdquo Food and ChemicalToxicology vol 50 no 10 pp 3709ndash3718 2012

[17] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[18] G Guisti and B Galanti ldquoColorimetric methodrdquo in Methodsof Enzymatic Analysis H U Bergmeyer Ed pp 315-23 VerlagChemie Weinheim Germany 1984

[19] J T Rogers and D K Lahiri ldquoMetal and inflammatory targetsfor alzheimers diseaserdquo Current Drug Targets vol 5 no 6 pp535ndash551 2004

[20] J T Rogers V Venkataramani C Washburn et al ldquoA role foramyloid precursor protein translation to restore iron home-ostasis and ameliorate lead (Pb) neurotoxicityrdquo Journal ofNeurochemistry pp 479ndash494 2016

[21] J S Jurenka ldquoAnti-inflammatory properties of curcumin amajor constituent of Curcuma longa a review of preclinical andclinical researchrdquoAlternativeMedicine Review vol 14 no 2 pp141ndash153 2009

[22] A S Bagad J A Joseph N Bhaskaran and A Agarwal ldquoCom-parative evaluation of anti-inflammatory activity of curcum-inoids turmerones and aqueous extract of Curcuma longardquoAdvances in Pharmacological Sciences vol 2013 Article ID805756 7 pages 2013

[23] V A Pavlov W R Parrish M Rosas-Ballina et al ldquoBrainacetylcholinesterase activity controls systemic cytokine levelsthrough the cholinergic anti-inflammatory pathwayrdquo BrainBehavior and Immunity vol 23 no 1 pp 41ndash45 2009

[24] H Wang M Yu M Ochani et al ldquoNicotinic acetylcholinereceptor 1205727 subunit is an essential regulator of inflammationrdquoNature vol 421 no 6921 pp 384ndash388 2003

[25] R PAGaykema S-MParkCRMcKibbin andL EGoehlerldquoLipopolysaccharide suppresses activation of the tuberomam-millary histaminergic system concomitant with behavior Anovel target of immune-sensory pathwaysrdquo Neuroscience vol152 no 1 pp 273ndash287 2008

[26] M Rosas-Ballina and K J Tracey ldquoCholinergic control ofinflammationrdquo Journal of Internal Medicine vol 265 no 6 pp663ndash679 2009

[27] Y Pollak A Gilboa O Ben-Menachem T Ben-Hur H Soreqand R Yirmiya ldquoAcetylcholinesterase inhibitors reduce brainand blood interleukin-1120573 productionrdquoAnnals of Neurology vol57 no 5 pp 741ndash745 2005

[28] K Ofek K S Krabbe T Evron et al ldquoCholinergic statusmodulations in human volunteers under acute inflammationrdquoJournal ofMolecularMedicine vol 85 no 11 pp 1239ndash1251 2007

[29] T J Searl and E M Silinsky ldquoMechanisms of neuromodulationas dissected using Sr2+ at motor nerve endingsrdquo Journal ofNeurophysiology vol 99 no 6 pp 2779ndash2788 2008

[30] H Zimmermann ldquoATP and acetylcholine equal brethrenrdquoNeurochemistry International vol 52 no 4-5 pp 634ndash6482008

[31] G Burnstock ldquoP2X ion channel receptors and inflammationrdquoPurinergic Signalling vol 12 no 1 pp 59ndash67 2016

[32] G Burnstock ldquoPurinergic signalling and neurological diseasesAn updaterdquoCNS and Neurological Disorders - Drug Targets vol16 no 3 pp 257ndash265 2017

[33] D Rial D R Lara and R A Cunha ldquoThe adenosine neuro-modulation system in schizophreniardquo International Review ofNeurobiology vol 119 pp 395ndash449 2014

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom

Medicinal ChemistryInternational Journal of

Hindawiwwwhindawicom Volume 2018

ToxicologyJournal of

Hindawiwwwhindawicom Volume 2018

PainResearch and TreatmentHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Arthritis

Neurology Research International

Hindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018

Drug DeliveryJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawiwwwhindawicom Volume 2018

AddictionJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

BioMed Research International

Emergency Medicine InternationalHindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Anesthesiology Research and Practice

Journal of

Hindawiwwwhindawicom Volume 2018

Pharmaceutics

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Infectious Diseases and Medical Microbiology

Hindawiwwwhindawicom Volume 2018

Canadian Journal of

Hindawiwwwhindawicom Volume 2018

Autoimmune DiseasesScientica

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

Submit your manuscripts atwwwhindawicom