Cerebroprotein hydrolysate:Innovation in the treatment of neurodegenerative disordersParveen Gupta*, Shailesh Yadav**, Kiran Kumar Singal***AbstractNeurodegenerative disorders are one of the leading causes of death and disability in both developing and developed countries.There are a number of neurotrophic drugs used in these disorders. Cerebroprotein hydrolysate is the latest one launched in morethan 40 countries. Its superiorty is because of different actions which help in faster and more complete nerve repair and growththanotherneurotrophicagents.Differentmechanismsincluderegulationandimprovementoftheneuronalmetabolism,modulationofthesynapticplasticity,neuronaldifferentiationandprotectionagainstischaemicandneurotoxiclesions,cerebroprotein hydrolysate reduces excitotoxic damage, blocks over-activation of calcium dependent proteases, and scavengesfree oxygen radicals.R E V I E W A R T I C L EJIACM 2014; 15(2): 132-3*Associate Professor, ***Asst. Professor, Department of Medicine, **Associate Professor, Department ofPharmacology;Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala - 134 203, Haryana.EpidemiologyIschaemic stroke, traumatic brain injury, vascular dementiaand Alzheimers disease (AD) collectively are responsiblefor a major part of morbidity and mortality in geriatric aswell as young adult population.StrokeranksasthethirdleadingcauseofdeathintheUnited States. It is now estimated that there are more than700,000 incident strokes annually and 4.4 million strokesurvivors1.In the USA on an average, approximately 1.7million people sustain a traumatic brain injury annually2.Roughly speaking, in the USA alone, 1,300/100,000 peoplesufferconcussionseachyear.Ofthese,300/100,000aretreated in emergency departments. Of these, 90/100,000are retained in the hospital. Around 25/100,000 die3. ADand other degenerative diseases that affect the cognitivefunctions in the elderly compromise the quality of life formore than 24 million people across the world4.Besidestheabove-mentionedillnesses,otherneurodegenerativedisorderslikeamyotrophiclateralsclerosis,Friedreichsataxia,Huntigtonsdisease,Parkinsonsdisease,andLewy-bodydiseaseposesomeofmodernmedicinesmostdifficultchallenges.Thecommon pathophysiologic feature in all these conditionsis the same, i.e., functional loss of neurons.Development, basic structure, and repair ofneuronsNeuron is the basic structural and functional unit of thenervoussystem.Althoughtherearesomevariationsdepending on the type of neurons, they all contain fourparts: cell body, dendrites, axon, and axon terminal. Theydevelop from the neural stem cells known as type 1 cellswhichproduceprogenycalledamplifyingneuralprogenitorcells(alsoknownastype2cells)whichproliferateanddifferentiateintomatureneurons.Tillrecent past it was believed that there is no way to repair adamaged neuron.One of the main goals of researchers is to develop drugs tostimulate areas of the brain to repair itself by replacing itsowncells5.Severaldrugslikeedaravone,citicoline,andpiracetamhavebeendevelopedbasedontheseneurotrophicfactors.Neurotrophicfactorsaresmallproteins that exert survival-promoting and trophic (derivedfrom the Greek meaning to nourish) actions on neuronal(or nerve) cells6. These neurotrophic factors are NGF (nervegrowth factor), BDNF (brain-derived neurotrophic factor),NT-3(neurotrophin-3),GDNF(glialcell-derivedneurotrophic factor), GAP-43 (growth associated protein 43)and CNFT (cilliary neurotrophic factor).Glial cells continue to undergo cell division in adulthoodandtheirabilitytoproliferateisparticularlynoticeableafterbraininjury(e.g.,stroke)7. Thisisnotthecasewithneurons;theycannotdivide,buttheyundergoalotofactivity after injury. Treatment of these neurodegenerativedisorders is changing at a remarkable pace. Interestingly,studies demonstrate that neurons in the adult brain havean unappreciated capacity for remodelling away from theactualinjury,andthattheseneuronsareattemptingtore-wire the brain following an injury8.Cerebroproteinhydrolysateisthelatestweaponinthephysiciansarmamentarium.Itisaneurotrophicdrug.Itconsistsofshortbiologicalpeptideswhichactlikeendogenous neurotrophic factors. Neurotrophic activitycan be detected upto 24 hours after a single injection. Ithas been approved in a number of European and Asiancountries.PharmacokineticsIt is given in a dose of 60 -180 mg once daily for 10 - 20days. It should be slowly perfused in 250 ml saline in 60 -120minutes.Maintenancedoses(30mg)canbegivenbyintramuscularroute.Itshouldnotbemixedwithbalancedaminoacidsolutionsinaninfusion.Doseofantidepressantsshouldbereducedifusedwithcerebroprotein hydrolysate.Adverse effects and contraindicationsStudies9,10 have revealed that most of the side effects areminor.Mostcommonsideeffectsincludeheadache,nausea,vertigo,increasedsweating,agitation,fever,hallucinations,confusion,andflu-likesyndrome.Contraindications include hypersensitivity, epilepsy andsevere renal impairment. Safety has not been establishedin pregnancy and lactation; so should be used cautiouslyin humans.Indicationsa) Acute ischaemic stroke.b) Traumatic brain injury.c) Vascular dementia.d) Alzheimers disease (AD).MechanismofactionandpharmacologicaleffectsCerebroprotein hydrolysate acts by:-a) Regulationandimprovementoftheneuronalmetabolism.b) Modulation of the synaptic plasticity.c) Neuronaldifferentiationandprotectionagainstischaemic and neurotoxic lesions.d) Cerebroproteinhydrolysatereducesexcitotoxicdamage, blocks over-activation of calcium dependentproteases, and scavenges free oxygen radicals.Cerebroprotein hydrolysate has been shown to counteractthe negative effect of the elevated FGF-2 on neurogenesisand neuromodulation11. This could be the mechanism forits beneficial effect in Alzheimers disease.Cerebroproteinhydrolysate-augmentedproliferation,differentiation,andmigrationofadultSVZneuralprogenitorcellsresultsinincreasednumberofneuralprogenitorcellsandneuroblaststocontributetoneurogenesis. This may be the mechanism for its beneficialeffect in acute ischaemic stroke and traumatic brain injury.Enhancement of neuronal survival is produced througheffectoncalpain.Thehyper-activationofcalpainisimplicated in a number of neurodegenerative disorders.Calpain is inhibited by Cerebroprotein hydrolysate.Neuromodulatory effect is produced by increasing GLUT-1 expression which is responsible for more than 90% ofglucose transport to brain12.Neuronal plasticity is produced by reduction of amyloidbeta accumulation, increased MAP 2 and synaptophysinsynthesis.Neuro-immunotrophic activity is produced by inhibitionof microglial activation and expression of IL-1 beta. Thisresults in reduction of inflammation.This drug can be given with other neuroprotective agentslikeedaravone,citicoline,andpiracetamsafely.Otherneurotrophicdrugsandnootropicsarenothavingasmuch broad spectrum of different actions as possessedbycerebroproteinhydrolysate.Thepatientsofneurodegenerative disorders can now be managed in abetter way with the advent of cerebroprotein hydrolysate.References1. GoldsteinLB,AdamsR,BeckerKetal.PrimaryPreventionofIschemicStroke.AStatementforHealthcareProfessionalsFromthe Stroke Council of the American Heart Association. Stroke 2001;32: 280-99.2. InjuryPrevention&Control:TraumaticBrainInjury.http://www.cdc.gov/traumaticbraininjury/(lastaccessedon30-nov-2011).3. Introductiontotraumaticbraininjury.TheNeurosurgeonsHandbook.In:SamandourasG,editor.Oxford:OxfordUniversityPress; 2010. p. 207-8.4. ThomasSV.AddressingproblemsofdementiainIndia.AnnalsofIndian Academy of Neurology 2011; 14(3): 147.5. Introductiontoneurogenesis.Availableathttp://neurogenesis.iord.org/ accessed on15th oct 2011.6. http://www.ceregene.com/neurotrophic.asp) last accessed on 30oct 2011.7. Ganongsetal.ReviewofMedicalPhysiology.In:Physiologyofnerve and muscle cells: Excitable Tissue: Nerve 23rd edi. 2010.8. Gopalan T.India: Neurons Key To Healing Of Brain Injuries Identified.August24,2010.ResearchNews[online]Availablefrom:http://www.medindia.net/news/Neurons-Key-To-Healing-Of-Brain-Injuries-Identified-73058-2.htm][last accessed on Nov 28 2011.9. Long J, Wei GZ, Xu ZB et al. Injection of cerebroprotein hydrolysatevscerebrolysinintreatingcerebrovasculardiseases.[Availablef r om: ht t p: / / en. cnki . com. cn/ Ar t i cl e_en/ CJ FDTOTAL-XYYL606.002.htm. Last accessed on March 07 2012.]10. Sui CM, Kam WC, Jia-Hong L et al. Systematic Review on the Efficacyand Safety of Herbal Medicines for Vascular Dementia. [Availablefrom:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250997.Last accessed on March 07 2012.]11. ChenHetal. TrophicfactorscounteractelevatedFGF-2-inducedinhibition of adult neurogenesis. Neurobiol Aging 2007; 28(8): 1148-62.12. Neuroscience Research 1999, 34: 217-24.J ournal, I ndian Academy of Clinical Medicine

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