Sex differences in Parkinson's disease and other movement disorders

Experimental Neurology xxx (2014) xxx–xxx

YEXNR-11683; No. of pages: 13; 4C:

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Experimental Neurology

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Review

Sex differences in Parkinson's disease and other movement disorders

Kara M. Smith ⁎, Nabila DahodwalaParkinson's Disease and Movement Disorders Center, 330 S. 9th St, 2nd Floor, Philadelphia, PA 19107, USA

Abbreviations: PD, Parkinson's disease; HD, Huntingtohormone replacement therapy; MPTP, 1-methyl-4-pdihydroxyphenylacetic acid; HVA, homovanillic acid; DADPN, diarylpropionitrile; SERM, selective estrogen recepto⁎ Corresponding author. Fax: +1 215 829 6606.

E-mail address: [email protected] (K.M. Sm

http://dx.doi.org/10.1016/j.expneurol.2014.03.0100014-4886/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: Smith, K.M., Dahodhttp://dx.doi.org/10.1016/j.expneurol.2014.0

a b s t r a c t
a r t i c l e i n f o
Article history:Received 20 November 2013Revised 7 March 2014Accepted 19 March 2014Available online xxxx

Keywords:Parkinson's diseaseHuntington's diseaseChoreaTicsTourette's syndromeSex differencesEstrogenTestosteroneSex chromosomeNeuroprotection

Movement disorders including Parkinson's disease (PD), Huntington's disease (HD), chorea, tics, and Tourette'ssyndrome (TS) display sex differences in disease susceptibility, disease pathogenesis, and clinical presentation.PD is more common in males than in females. Epidemiologic studies suggest that exposure to endogenous andexogenous estrogen contributes to these sex differences. There is extensive evidence that estrogen preventsdopaminergic neuron depletion induced by neurotoxins in PD animal models and therefore is neuroprotective.Estrogen may also decrease the efficacy of other neuroprotective substances such as caffeine in females but notmales. Sex chromosomes can exert effects independent of sex steroid hormones on the development and main-tenance of the dopamine system. As a result of hormone, chromosome and other unknown effects, there aresexual dimorphisms in the basal ganglia, and at the molecular levels in dopaminergic neurons that may lead todistinctmechanisms of pathogenesis inmales and females. In this review,we summarize the evidence that estro-gen and selective estrogen receptor modulators are neuroprotective in PD and discuss potential mechanisms ofaction. We also briefly review how sex differences in basal ganglia function and dopaminergic pathways mayimpact HD, chorea, and tics/Tourette's syndrome. Further understanding of these sex differences may lead tonovel therapeutic strategies for prevention and treatment of these diseases.

© 2014 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Parkinson's disease risk in clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Animal studies of neuroprotection by estrogen and progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Neuroprotection by selective estrogen receptor modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Studies of neuroprotection by male hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Mechanisms of neuroprotection by estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Interaction between caffeine and estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Sexual dimorphisms in dopaminergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Sex chromosomes and Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Huntington's disease and sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Chorea gravidarum and Sydenham's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Tics and Tourette's syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

n's disease; TS, Tourette's syndrome; SNpc and SNpr, substantia nigra pars compacta and pars reticulata; DA, dopamine; HRT,henyl-1,2,3,6-tetrahydropyridine; MA, methamphetamine; 6-OHDA, 6-hydroxydopamine; DA, dopamine; DOPAC,T, dopamine transporter; VMAT2, vesicular monoamine transferase 2; TH, tyrosine hydroxylase; PPT, propyl-pyrazole-triol;r modulator; KO, knock out; PSP, progressive supranuclear palsy; MAO, monoamine oxidase inhibitor.

ith).

wala, N., Sex differences in Parkinson's disease and other movement disorders, Exp. Neurol. (2014),3.010

http://dx.doi.org/10.1016/j.expneurol.2014.03.010

mailto:[email protected]


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2 K.M. Smith, N. Dahodwala / Experimental Neurology xxx (2014) xxx–xxx

Introduction

Movement disorders are a diverse group of neurologic conditionsthat can be grouped broadly into hyperkinetic and hypokineticdisorders. There are significant sex differences in the pathophysiology,epidemiology and clinical manifestations of many of these diseases.The unifying pathophysiology of these various diseases relates to dys-function of the basal ganglia and interconnected pathways. The basalganglia are compromised of the caudate and putamen, also knowntogether as the striatum, the globus pallidus, the subthalamic nucleus,and the substantia nigra pars compacta and pars reticulata (SNpc andSNpr), which contain dopaminergic neurons. Dopamine (DA) is one ofthe major regulatory neurostransmitters of the basal ganglia, anddopaminergic system dysfunction can manifest in highly divergentclinical presentations.

The most common disease of dopamine dysfunction is Parkinson'sdisease (PD). There are sex disparities in PD, with a higher incidenceand prevalence of PD in men. Sexual dimorphisms in non-diseasedbasal ganglia and substantia nigra may partly explain this sex-specificrisk (Beyer et al., 1991). Estrogenmay also account for someof these dif-ferences, andwewill review the evidence that estrogen is neuroprotec-tive to the dopaminergic system. In addition, chromosome differencesmay contribute to the sex differences noted in PD, with interplaybetween chromosomal factors and gonadal hormone factors. We willreview the evidence available that implicates the male Y chromosomein increased risk of PD in men. Tourette's syndrome (TS) and tics, bothhyperkinetic movement disorders, are also much more common inmen than women. Conversely, the genetic movement disorder of doparesponsive dystonia occurs more often in women due to higher pene-trance, and chorea associated with pregnancy occurs exclusively inwomen.Wewill also briefly review the limited literature that describespotential mechanisms by which sex may impact disease susceptibility,disease pathogenesis, and clinical presentation of these other move-ment disorders.

Parkinson's disease risk in clinical studies

PD occurs more often in men than in women, with a meta-analysisreporting an increased relative risk of 1.5 (Wooten et al., 2004). PDincidence rates are twice as high in men compared to women at allages in an Italian population, and 91% higher in men in the KaiserPermanente Medical Care Program in Northern California (Baldereschiet al., 2000). Because estrogen is known to exert effects on dopaminesynthesis and function, clinical studies have focused on the correlationbetween estrogen exposure and PD risk. Rocca and colleagues evaluatedthe risk of PD (or parkinsonism) in the Mayo Clinic Cohort Study ofOophorectomy and Aging, which included over 2000 patients andcontrols. In women who had undergone unilateral oophorectomy, therisk of PD was increased, but was only statistically significant if the sur-gery was performed before age 42. In women who underwent bilateraloophorectomy, there was a significantly increased risk of PD with ahazard ratio of 1.8 (Rocca et al., 2008). In a case-control study, PD wasassociated with a lower cumulative estrogen exposure during life, orshorter fertile lifespan (R S-P et al., 2009; Ragonese et al., 2004). Similarly,increased length of endogenous estrogen exposure was associatedwith older age of onset and less severe motor impairment in a cross-sectional study of women with PD (Cereda et al., 2013). Women withPD were less likely to have used HRT, and postmenopausal use of HRTcorrelated with lowered PD risk in another case-control study (Currieet al., 2004). However, this was not the case in a group of women studiedbyMarder and colleagues where the use of HRT did not decrease the riskof PD, but did decrease the risk of developing PDwith dementia (Marderet al., 1998). Similarly, Simon and colleagues didnotfind an increased riskof PD associated with any endogenous or exogenous estrogen exposuremarker in the Nurses' Health Study (Simon et al., 2009). Therefore,although both endogenous and exogenous estrogen can be potentially

Please cite this article as: Smith, K.M., Dahodwala, N., Sex differences in Pahttp://dx.doi.org/10.1016/j.expneurol.2014.03.010

protective, it remains unclear to what degree estrogen exposure contrib-utes to the risk of developing PD in the majority of women with thisdisease.

An epidemiologic phenomenon possibly related to both PD andestrogen exposure is pesticides. Exposure to various pesticides mayincrease the risk of PD (Brown et al., 2006). Moreover, many pesticideseither mimic or block estrogen. While a causal relationship betweenpesticide exposure, estrogen and PD risk has not been established, theunderlying mechanisms may be elucidated by studying the effect ofpesticides on estrogen pathways and sex differences in exposure-related risk.

Estrogenmay also affect the clinical presentation of womenwith PD.Estrogen has been shown to both improve and worsen symptoms.Much of the older literature in this field points to estrogen as an anti-dopaminergic agent (Koller et al., 1982; Quinn and Marsden, 1986). Acase was reported in which PD symptoms improved with pharmacolog-ically inducedmenopause (Session et al., 1994). On the other hand, thereare more recent and numerous reports of estrogen improving the motorsymptoms of PD. In a randomizedplacebo-controlled study of oral conju-gated estrogen, patients receiving estrogen had significantly more “on”time and a clinically significant decrease in motor scores over 8 weeksof treatment (Tsang et al., 2000). In the POETRY study, a pilot study ofHRT in postmenopausal women with PD, there was a trend towardimprovement in motor scores, however this did not reach statistical sig-nificance and the study was limited by under-enrollment (Anon, 2011).

Animal studies of neuroprotection by estrogen and progesterone

Estrogen is likely a contributor to the sex differences observed in PDprevalence. As discussed above, longer estrogen exposure during afemale's lifetime may decrease the risk of PD. Most women developPD after menopause, which suggests that estrogen withdrawal may berelated to the pathogenesis of the disease. Furthermore, estrogenappears to protect against dopaminergic neuron loss in both diseaseand non-disease states. It has been shown that dopaminergic neuronloss occurs after ovariectomy in rats and primates (Le Saux and DiPaolo, 2006) and this can be reversed with administration of estrogencompounds. A study in monkeys demonstrated that estradiol alteredDA metabolism and transporter uptake in the brain after surgicallyinduced menopause (Morissette and Di Paolo, 2009). Interestingly,this post-ovariectomy DA loss also manifests clinically as decreasedspontaneous locomotor activity in rats, which can be reversed withadministration of exogenous estrogen (Ohtani et al., 2001). Althoughthe clinical manifestations of post-menopausal DA loss have not beenstudied in non-parkinsonianhuman females, a small pilot study showedthat estrogen replacement therapy in non-parkinsonian women in-creased putamenal dopamine active transporter (DAT) as measuredby TRODAT SPECT scan (Gardiner et al., 2004). With evidence pointingmore consistently to estrogen as a pro-dopaminergic agent, as well asexciting implications for estrogen as a neuroprotective agent in ische-mia and other neuropathologic processes, there has been a greatdeal of research into estrogen's potential neuroprotective effects ondopaminergic neurons. The majority of this research has utilizedanimal neurotoxin-mediated models of PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a by-product of meperidinesynthesis that is well known to cause parkinsonism in humans, and isprobably the most widely utilized animal model for PD. Male mice aremore sensitive to MPTP, in terms of striatal dopaminergic neuron loss,than female mice (Dluzen et al., 1996). Methamphetamine (MA) alsocauses degeneration of striatal dopaminergic neurons in animals andhumans, and has a greater negative effect on male mice compared tofemalemice (Miller et al., 1998). If estrogen accounts for this differentialsusceptibility, then exogenous estrogen administration should be ableto further protect from DA neuron loss in these PD animal models.This hypothesis has been studied extensively and the results aresummarized in Tables 1.1–1.4. Overall, certain formulations of estrogen

rkinson's disease and other movement disorders, Exp. Neurol. (2014),


Table 1.1Studies of the neuroprotective effects of selective estrogen receptor modulators in neurotoxin animal models of Parkinson's disease.

Author, year Neurotoxin model SERM agent, dosea Outcome measuresb Results

Grandbois et al. (2000) MPTP Raloxifene, 5 mg/kg DA, DOPAC, HVA concentrations Prevented reduction (protective) of DA and metabolitesCallier et al. (2000) MPTP Raloxifene, 1 or 5 mg/kg SNpc DAT specific binding and mRNA Higher but not lower dose was protectiveDluzen et al. (2001) MA Tamoxifen 5 mg pellet DA, DOPAC, concentration Protective in intact males and femalesDluzen et al. (2001) MA Tamoxifen, 5 mg pellet DA, DOPAC concentration Tamoxifen eliminates neuroprotective effect of estrogenGao and Dluzen (2001) MA Tamoxifen, 5 mg pellet DA concentration and output (in vitro superperfusion system) Tamoxifen eliminates neuroprotective effect of estrogenRamirez et al. (2003) MPTP Raloxifene, 5 mg/kg DA concentration, MPP + concentration No protection in striatal DA content, no change in MPTP metabolism as assessed by

MPP + concentrationD'Astrous et al. (2004a) MPTP PPT, DPN DA, DOPAC concentration, striatal DAT specific binding Only PPT was protectiveMickley and Dluzen (2004) MA Tamoxifen, 12.5–500 μg DA, DOPAC concentration, behavioral assessment Protective of DOPAC/DA ratio, but not DA concentration for all doses; 500 μg dose

led to significantly increased center time subscore of animal activity behavioral scoreD'Astrous et al. (2005a) MA Tamoxifen, 2.5, 125, 500 μg DA concentration, DAT and VMAT2 specific binding,

preproenkephalin mRNAAll doses of tamoxifen protected DA and VMAT2, but not DAT except at highest doses

Bourque et al. (2007) MA Tamoxifen, 12.5 or 50 μg DA, HVA, VMAT2 binding and mRNA, preproenkephalin mRNA High but not low doses of tamoxifen was protectiveMorissette et al. (2008) MPTP Tamoxifen, 1 mg/kg DA, DOPAC, HVA concentrations Tamoxifen protected in male mice in dose-dependent fashion, did not block protective

effects of estrogen except for a slight decrease in DOPAC concentration.Baraka et al. (2011) 6-OHDA Tamoxifen (5 mg/kg), raloxifene

(5 mg/kg), PPT, DPNDA, DOPAC, HVA concentrations 17β-estradiol, raloxifene, PPT were protective

McFarland et al. (2013) 6-OHDA AC-186 (ERβ agonist) Striatal and SN TH immunoreactivity, TNFα and MCP-1,behavioral assessments

In males but not females, AC-186 was protective for behavioral deficits, striatal and SN DAneuron count. The increase in peripheral and brain homogenate TNFα was prevented byAC-186. MCP-1 increased peripherally but not in brain after 6-OHDA and did not decreasewith AC-186.

Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MA, methamphetamine; 6-OHDA, 6-hydroxydopamine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; DAT, dopamine transporter; VMAT2, vesic-ular monoamine transferase 2; TH, tyrosine hydroxylase; PPT, propyl-pyrazole-triol; DPN, diarylpropionitrile.

a SERM agents were administered before, concurrently with, and after neurotoxin treatment.b Outcomemeasures refer to concentrations in striatum unless otherwise specified as measured by post-mortem HPLC for DA, DOPAC, HVA concentrations, [125I]RTI-121 and [3H] dihydrotetrabenazine specific binding autoradiography on brain

tissue sections post-mortem for DAT and VMAT2 binding respectively, in situ hybridization histochemistry for DA T, VMAT2 and preproenkephalin mRNA.

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as:Smith,K

.M.,D

ahodwala,N

.,Sexdifferences

inParkinson's

diseaseand

othermovem

entdisorders,Exp.Neurol.(2014),



Table 1.2Studies of the neuroprotective effects of 17β-estradiol in neurotoxin animal models of Parkinson's disease.

Author, year Neurotoxin model Dose/formulationa Outcome measuresb Results

Dluzen et al. (1996) MPTP 1 mg pellet DA concentration Prevented reduction (protective)Dluzen et al. (1997) 6-OHDA 1 mg pellet DA and DOPAC concentrations Protective of DA. Decreased DOPAC concentration in non-lesioned side and no

difference in lesioned side.Miller et al. (1998) MPTP, MA 1 mg pellet DA, DOPAC, HVA concentrations, GFAP Protective in ovariectomized but not 2 year old intact femalesArvin et al. (2000) MPP+ 40 μM Dopamine release (in-vivo via electrochemistry,

in-vitro via superperfusion)Decreased dopamine release

Callier et al. (2000) MPTP 1 μg BID for 10 days DA, DOPAC, HVA concentrations, DAT specific binding andmRNA levels

Protection of DA, DOPAC, HVA but not DAT binding or mRNA in SNpc

Disshon et al. (2000) MPP+ 1 mg pellet DA and DOPAC concentration, DA release (via in-vivo microdialysis) Protection in females but not malesGrandbois et al. (2000) MPTP 1 μg BID for 10 days DA, DOPAC, HVA concentrations Protection of all markersCallier et al. (2001) MPTP 1 μg BID for 10 days Striatal DAT specific binding and SNpc DAT mRNA Protection of striatal DAT but not complete protection of SNpc DATDluzen et al. (2001) MPTP 1 mg pellet DA, DOPAC concentration ProtectionDluzen et al. (2001) MPTP 1 mg pellet DA concentration ProtectionGao and Dluzen (2001a) MA 0.1 mg pellet DA concentration and output (via in-vitro superperfusion system) Protection when treated before but not after MA exposureGao and Dluzen (2001b) MA 0.1 mg pellet DA concentration and output (via in-vitro superperfusion system) No protection in gonadectomized malesDigiorgio et al. (2002) Ibotenic acid 30 μg every other dayc SNpr TH immunoreactivity Protection of DA neuron countDluzen et al. (2002) MA 1 mg pellet DA concentration Protective in females only (males had acute toxic effect with bradycardia)Ekue et al. (2002) MPTP 1 μg BID for 10 days DA, DOPAC, HVA concentrations, DAT and VMAT2 specific binding,

SN DAT mRNAProtective of striatal and SN markers

D'Astrous et al. (2003, 2005a) MPTP 1 μg BID for 10 days DA, DOPAC, HVA concentrations, SN DAT and TH mRNA Protective of striatal DA concentration and turnover, protective of SN markersFerraz et al. (2003) 6-OHDA 0.5 mg capsule SNpc TH immunoreactivity No protection (measured at 45 days)Murray et al. (2003) 6-OHDA 0.5 mg pellet DA concentration, SN TH immunoreactivity Protection of striatal DA in females but not malesMyers et al. (2003) MA 30 nMd DA release (in-vitro superperfusion system) Reduced dopamine release in males and femalesRamirez et al. (2003) MPTP a) 12 μge DA concentration, MPTP metabolism a) Single high dose did not protect DA

b) 0.1, 0.32, 1 or 3.2 μg BID b) Dose-dependent protection up to 1 μg (similar effect with sacrificing mice at2, 4, or 6 days post-MPTP)No difference in MPTP metabolism

D'Astous et al. (2004b) MA 10 μg single injectionf DA, DOPAC concentration, DAT specific binding, SN DAT mRNA Increased protection of DA with increasing time before MA, significant at 12 h.DAT binding protected at all time intervals, SN DAT mRNA protected only at 24 h.

Shunghrue et al. (2004) MPTP 100 μg Striatal TH immunoreactivity ProtectionAnderson et al. (2005) MA 0.1 mg pellet DA concentration In mice with neonatal gonadectomy, there was protection only in females with

testosterone supplementation, not in males. In female mice with pre-pubertalgonadectomy, there was no protection with or without testosterone treatment

Jourdain et al. (2005) MPTP 2 μg BID for 10 days DA, DOPAC, HVA concentrations, DAT and VMAT2 specific binding,DAT, VMAT2, TH mRNA levels

Protection of striatal DA, DOPAC, HVA. Protection of striatal DAT and VMAT2binding, and SN VMAT2 mRNA.

Tripanichkul et al. (2006) MPTP 2 μg BID TH immunoreactivity Protection of SN TH neurons and striatal TH fibers. Attenuation of microglialand astrocyte activation.

Xu (2006) MPTP 1 mg pellet DA, DOPAC concentration Estradiol alone protected striatal DA and DOPAC, but estrogen attenuated theprotective effect of caffeine

Ferraz et al. (2008) 6-OHDA 1 mg pellet DA, DOPAC, HVA, SNpc TH immunoreactivity No protection of striatal DA or metabolites, or TH positive neurons in SNpcMorissette et al. (2008) MPTP 1 μg BID DA, DOPAC, HVA concentrations Protection in wild type but not ERα or ERβ knock outsOokubo et al. (2008) MPTP 0.05 or 0.2 mg/kg BID for

10 days, or 0.5 or 2 mg/kg acutelyDA, DOPAC, HVA concentrations; striatal TH, DAT and GFAP protein(by Western blot)

No protection by low doses. Acute high dose prevented reduction of DOPAC butnot DOPA or HVA, and protected striatal TH and DAT protein levels.

Baraka et al. (2011) 6-OHDA 0.1 mg/kg DA, DOPAC, HVA concentrations, behavioral assessment, glutathioneperoxidase activity, caspase-3 activity

Protective increase in dopamine and metabolites, increase in GPx activity,decrease in nigral caspase-3 activity, improved behavioral outcomes

Cordellini et al. (2011) 6-OHDA 400, 800 or 1600 μg capsules DA, DOPAC concentrations in striatum and SNpc Protection only at 400 μg in striatal DA, no protection in SNpc

Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MA, methamphetamine; MPP+, 1-methyl-4-phenylpyridinium; 6-OHDA, 6-hydroxydopamine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid;DAT, dopamine transporter; VMAT2, vesicular monoamine transferase 2; PPT, propyl-pyrazole-triol; DPN, diarylpropionitrile; SNpc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata. GFAP, glial fibrillary acidic protein.

a Estrogen was administered before, concurrently with, and after neurotoxin treatment unless otherwise specified below.b Outcomemeasures refer to concentrations in striatum unless otherwise specified as measured by post-mortem HPLC for DA, DOPAC, HVA concentrations, [125I]RTI-121 and [3H] dihydrotetrabenazine specific binding autoradiography on brain tissue

sectionspost-mortem forDATandVMAT2binding respectively, in situhybridizationhistochemistry forDAT, VMAT2andpreproenkephalinmRNA.GFAPmeasuredusingELISA immunoassay.MPTPmetabolismwas assessed viaMPP+measuredusing liquidchromatography mass spectroscopy.

c Estrogen administered only after toxin exposure.d Co-infusion of estrogen and toxin.e Single dose before, within 24 h of toxin.f Single dose 24, 12 and 0.5 h before toxin.

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.M.,D

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.,Sexdifferences

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diseaseand

othermovem




Table 1.3Studies of the neuroprotective effects of 17α-estradiol, estradiol and progesterone in Parkinson's disease.

Author, year Steroid hormone Neurotoxin model Timing of experimental agent andtoxin exposure

Outcome measuresa Results

Callier et al. (2000) 17α-Estradiol MPTP Before, during and after DA, DOPAC, HVA concentrations; DAT specificbinding and mRNA levels

No protection

Grandbois et al. (2000) 17α-Estradiol MPTP Before, during and after DA, DOPAC, HVA concentrations No protectionDluzen et al. (2001) 17α-Estradiol MPTP Before, during and after DA, DOPAC concentrations No protectionRamirez et al. (2003) 17α-Estradiol MPTP 24, 2, 0.75 h before DA concentration No protectionD'Astous et al. (2005b) 17α-Estradiol MPTP 24 h before DA, DAT and VMAT2 concentrations,

preproenkephalin mRNA levelNo protection

Yu and Liao (2000) Estradiol benzoatee MA Daily for 3 days before MA DA, DOPAC, HVA concentrations ProtectionYu et al. (2002) Estradiol benzoatee MA Daily for 3 days before MA DA, DOPAC concentrations No protection in males or females GDX at 4 weeks,

protection in mice GDX at 6 weeks including withtamoxifen concurrently

Gajjar et al. (2003) Estradiol benzoate MA Before (24, 12, 0.5 h) or after(15, 30, 60 or 120 min)

DA, DOPAC concentrations Protection before but not if injected after MA

Mickley and Dluzen (2004) Estradiol benzoate MA 24 h before MA DA, DOPAC concentrations, behavioral assessment All doses protected DA, DOPAC. Highest dose increasedstereotypy time.

D'Astous et al. (2005c) Estradiol benzoate MA 24 h before MA DA concentration, DAT and VMAT2 specific binding,preproenkephalin mRNA level

Protection of DA, DAT, VMAT2, reduction ofpreproenkephalin

Liu and Dluzen (2006) Estradiol benzoate MA 1 week after MA, before a secondinjection of MA

DA, DOPAC concentrations No protection against a second MA injection(in an impaired striatum)

Liu et al. (2008) Estradiol benzoate MPTP Before, during and after DA, DOPAC, HVA concentrations, SN pc THimmunoreactivity, midbrain TH, DAT and Bcl-2mRNA (via RT-PCR)

Protection of all markers

Yu and Liao (2000) Progesterone, 0.467 mg MA Daily for 3 days before DA, DOPAC, HVA concentrations Protection alone and combined with estradiol benzoateCallier et al. (2001) Progesterone, 2 μg MPTP Before, during and after SNpc DAT specific binding and mRNA ProtectionGrandbois et al. (2000) Progesterone, 1 μg MPTP Before, during and after DA, DOPAC, HVA concentrations ProtectionYu et al. (2002) Progesterone, 0.47 μg MA Before, during and after DA, DOPAC concentrations Protection (combined with estradiol benzoate)Morissette et al. (2008) Progesterone, 2 μg MPTP Before, during and after DA, DOPAC, HVA concentrations Protection

Abbreviations:MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; DAT, dopamine transporter; VMAT2, vesicularmonoamine transferase 2, SNpc, substantia nigra parscompacta; GDX, gonadectomized.

a Outcome measures refer to striatum unless otherwise specified.e Single dose before, within 24 h of toxin.

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.M.,D

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.,Sexdifferences

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Table1.4

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have been shown to have a neuroprotective effect against a varietyof toxic substances (MPTP, 1-methyl-4-phenylpyridinium (MPP), MA,6-hydroxydopamine (6-OHDA)). Neuroprotection after neurotoxinexposure in these animal studies is defined in two ways: 1) preventionof reduction in striatal dopamine and its related metabolitesdihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA); and2) maintenance of dopamine neuronal integrity as measured by dopa-mine active transporter (DAT), vesicular monoamine transporter2 (VMAT2) specific binding and mRNA, or tyrosine hydroxylase (TH)immunoreactivity. Animals were treated with estrogen compounds atdifferent time points including before, simultaneously with, and aftertoxin treatment. Results demonstrate that estrogen treatment needsto precede toxin administration to observe a protective effect. Treat-ment after the toxic insult cannot reverse the injury. The majority ofthe studies utilized male mice or female mice that had been ovariecto-mized at 6 weeks old. Neuroprotective effects have been shown mostconsistently with 17β-estradiol. This stereoisomer has the highestaffinity for the estrogen receptor, suggesting that the neuroprotectiveeffects are receptor-mediated (Kuiper et al., 1997). Other estrogencompounds with lower affinity for the estrogen receptor include17α-estradiol, estriol and estone. Our review of the literature yielded31 studies, of which 27 demonstrated that 17β-estradiol has some neu-roprotective benefit (Table 1.2). Themajority of successful experimentsadministered low doses of 17β-estradiol mimicking physiologic levels(1 μg, usually as a slow release pellet) 1–10 days before toxin adminis-tration. One study in contrast reported a neuroprotective effect usinghigh but not low dose 17β-estradiol (Ookubo et al., 2008).While striataldopamine and dopamine metabolite concentrations were more consis-tently protected, the few studies using markers of SNpc DA neuronalloss did not consistently show a protective effect. For instance, Ferrazand colleagues did not find a decrease in SNpc dopamine neuron lossafter treatment with 6-OHDA (Ferraz et al., 2003; Ferraz et al., 2008).Estrogen may therefore alter the release or metabolism of dopamine inthe striatum without directly affecting SN dopamine neuronal loss.Further research is needed to distinguish this neuromodulatory effectfrom a true neuroprotective effect. The results in males were also lessconsistent than in females. All studies using females ovariectomized at6 weeks showed neuroprotectionwhen 17β-estradiol was administeredbefore the toxin exposure. One study using females ovariectomizedbefore puberty was negative (Anderson et al., 2005) and another studyusing two year old intact femaleswas negative (Miller et al., 1998). Inter-estingly, studies using a similar protocol but using theMA toxicitymodelinstead of MPTP showed different results for male and female mice. Lowdose pellet formulation of 17β-estradiol protected DA concentrations infemales but notmales (Anderson et al., 2005; Dluzen et al., 2001; Dluzenet al., 2002; Gao and Dluzen, 2001). Therefore, it seems that MA hasdifferent mechanisms of action in males and females that can be differ-entially affected by estrogen administration resulting in neuroprotectionin females only.

Estrogen compounds with lower affinity for the estrogen receptorinclude 17α-estradiol, estriol and estrone. Although 17α-estradiol haspreviously demonstrated neuroprotective effects in other experimentalmodels of brain injury, it failed to show neuroprotection in male andfemaleMPTP treatedmice (Table 1.3). A single study showed protectionof all markers assayed with estradiol in ovariectomized females (Liuet al., 2008). Two studies report that estrone does not protect striataldopamine concentration, DAT binding or substantia nigra VMAT2mRNA levels (Jourdain et al., 2005; Ookubo et al., 2008). Estriol failedto protect DAT and VMAT2 specific binding in another study (Jourdainet al., 2005). There were 7 total studies of estradiol benzoate, and allthat used the compound after toxin administration reported a neuro-protective effect (Table 1.3). Furthermore, Yu and colleagues showedthat estradiol benzoate protected DA and DOPAC concentrationsin males or females gonadectomized at 6 weeks but not at 4 weeks(Yu et al., 2002). Thus, the timing of exposure to endogenous steroidsduring development appears to influence the response to exogenous



7K.M. Smith, N. Dahodwala / Experimental Neurology xxx (2014) xxx–xxx

steroids later in life. Progesterone acts on its own receptors, but depend-ing on tissue location and estrogen levels, it has interconnected effectson estrogen pathways. In MPTPmodels, progesterone protected againstdecreases in striatal DA, DOPAC and HVA concentrations (Grandboiset al., 2000) and DAT specific binding (Callier et al., 2000). Morissetteand colleagues combined physiologic doses of 17β-estradiol andprogesterone and demonstrated that while there was no additiveneuroprotective effect, progesterone did not block the neuroprotectiveeffect of 17β-estradiol (Morissette et al., 2008). In MA models, proges-terone prevented striatal DA loss at low doses inmales gonadectomizedat 6 weeks, but only at high doses in ovariectomized females (Yu et al.,2002). Progesterone may therefore be a promising neuroprotectiveagent, either in isolation at physiologic doses or in combination withestrogen. This needs to be studied further to elucidate the differenteffects between dosage regimens, sexes and neurotoxin models.

Neuroprotection by selective estrogen receptor modulators

Tamoxifen and raloxifene are selective estrogen receptors modula-tors (SERMs) used clinically to treat breast cancer and osteoporosis,respectively. These compounds act as estrogen receptor antagonists inthe target tissue of these diseases, but can also act as estrogen receptoragonists in other tissues. There are also experimental compounds thattarget estrogen receptor α or β specifically, and new compounds arecurrently being developed that could selectively stimulate humanestrogen receptors without causing unwanted side effects that wouldlimit clinical utility. The current literature supports both tamoxifenand raloxifene as neuroprotective agents in PD animal models; 10of 13 articles reported protective effects (Table 1.1) A single studyreported that tamoxifen blocked the neuroprotective effect of17β-estradiol, however this study used higher doses of tamoxifenthan other studies reviewed (Gao and Dluzen, 2001). Interestingly,this finding has clinical relevance. In a cohort study of 15,440 womenwith breast cancer, women on tamoxifen had an increased hazardratio for PD (HR = 5.1), but only within a delayed period of 4 to6 years after initiation of treatment (Latourelle et al., 2010). Thus,tamoxifen may increase the risk of PD when used in higher dosage.

In summary, the neuroprotective or neurotoxic effects of estrogensand SERMs depend on several variables including specific estrogen orSERM compound, dose and duration of treatment, and sex. Anotherkey factor is timing of hormone administration relative to gonadaldevelopment or gonadectomy. It is therefore important whether thesesteroid compounds are given early or late in life and pre- or post-menopause. Furthermore, long terms effects have yet to be evaluated,as most of the animal studies involve sacrificing the subjects withindays of toxin exposure. Finally, animal neurotoxin models of PD havean entirely distinct mechanism of disease pathogenesis from idiopathicPD in humans. Estrogen may be protective in these neurotoxin modelsspecifically by decreasing the uptake of the toxin into dopaminergicneurons (Le Saux and Di Paolo, 2006). Studies using genetic animalmodels would be helpful to characterize the ability of estrogen to pro-tect dopamine neurons in the presence of disease-causing or disease-susceptibility mutations. In order to design human clinical trials, theeffects on the healthy and diseased dopaminergic system also needsto be more clearly defined, and risks of peripheral systemic side effectsof hormonal therapies considered. It therefore remains unclear howestrogen's neuroprotective effects may be translated from animalmodels to humans.

Studies of neuroprotection by male hormones

Androgens including testosterone and dehydroepiandrosterone(DHEA) failed to show neuroprotection (Table 1.4). In both MA andMPTP-treated mice, pre-treatment with androgen compounds actuallyincreased the detrimental effects on markers of striatal DA integrity inmales but not females (Ekue et al., 2002). The detrimental effect of


testosteroneon striatal dopamine is eliminated by gonadectomy, but re-stored by subsequent estrogen treatment, suggesting that testosteronearomatized to estrogen in the brain is actually responsible (Gillies andMcArthur, 2010). From a clinical perspective, testosterone supplemen-tation has been investigated as an adjunct therapy for motor and non-motor symptoms of PD. Men with PD were found to have similar tohigher rates of testosterone deficiency than the general population,but supplemental testosterone failed to show significant improvementin motor or non-motor outcomes (Okun et al., 2006). However, thisstudy was designed to look at symptomatic benefit using a patientquestionnaire, and was not intended to look at neuroprotection.

Mechanisms of neuroprotection by estrogens

Researchers have proposed several different pathogenic mecha-nisms in idiopathic PD, including a multiple hit hypothesis. Thesemechanisms include oxidative stress, mitochondrial dysfunction,glutamate excitotoxicity and dysfunction of organelle trafficking anddegradation pathways. Estrogen's neuroprotective effectsmay bemedi-ated by some of these samemechanisms, making it relevant not only toexperimental neurotoxin-mediated PDmodels but also to idiopathic PDpathogenesis (Fig. 1). Estrogen produces downstream effects by bothnon-genomic actions, such as activation of signal pathways, and geno-mic effects involving gene transcription. Both ERα and ERβ receptorslocalize in the mouse striatum (Kuppers and Beyer, 1999). Al-Sweidiand colleagues studied ERα and ERβ knock out (KO) mice, and demon-strated that ERKOα mice were more sensitive to the striatal effects ofMPTP than wild type or ERKOβ mice. 17β-estradiol failed to protectstriatal DAT or VMAT2 specific binding in ERα or ERβ KO mice treatedwith MPTP (Al-Sweidi et al., 2011). They concluded that ERα plays theprimary role in mediating neuroprotection and that ERβ plays asupportive role. This is further supported by studies utilizing propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPT) as specific ERα andERβ agonists, respectively, that foundPPT but not DPTwas neuroprotec-tive (Baraka et al., 2011).

17β-estradiol acts on the MAPK/ERK and P13K/Akt pathways, andexerts neuroprotective effects from glutamate, H2O2, and β-amyloidtoxicity through these pathways. These signal cascades function broadlyin cell survival. MAPK/ERK activation leads to inhibition of pro-apoptotic proteins such as BAD and GSK3β. GSK3β in particular hasbeen shown to mediate toxin-induced striatal neuron death. It is aconstitutively active protein kinase that is inhibited by Akt via phosphor-ylation at serine residues. MPTP decreases GSKβ phosphorylation, there-by allowing GSK3β to remain active which leads to neuronal death.MPTP also decreases the Bcl-2 (pro-survival):BAD (pro-apoptotic)ratio. A specific ERα agonist (PPT), and to a lesser degree an ERβ agonist(DPT), were able to block both of these effects of MPTP (Bourque et al.,2009). The other neurotoxin models of PD, 6-OHDA and MA, also affectAkt and GSK3β. Importantly, there is evidence that these same signalcascade pathways play a role in genetic forms of PD such as parkinmutations. One study utilizing parkin null mice found that activation ofthese neuroprotective cellular pathways by estrogen was dependent onthe presence of parkin. Treatment of wild-type but not parkin-null mid-brain cell cultureswith estradiol led toMAPK, Akt, and GSK3β activation,increased TH neuron counts, and decreased apoptosis (Rodriguez-Navarro et al., 2008). Of note, GSK3β is also implicated in the pathogen-esis of neurodegenerative diseases with tau pathology, such as progres-sive supranuclear palsy (PSP). GSK3β phosphorylates tau, which leadsto microtubule dysfunction, disrupted intracellular protein trafficking,formation of neurofibrillary tangles, and neuronal death (Goodenoughet al., 2005). PSP also exhibits a male predominance clinically, so it isrelevant that GSK3β is inhibited by estrogen via the P13K/Akt cascade.Another estrogen receptor-mediated mechanism of neuroprotectionmay be increased expression of neurotrophic factors, such as glial cellline-derived neurotrophic factor (GDNF). Campos and colleagues dem-onstrated that 17β-estrogen increases GDNF levels in SN and striatum,




and that protection of dopaminergic neurons from 6-OHDA wasdependent on GDNF expression (Campos et al., 2012).

In addition to these signal cascade effects, estrogen could impact PDpathogenesis via its influence on mitochondrial function and responseto oxidative stress. 17β-estradiol reduces toxicity from glutamate, su-peroxide anions, and hydrogen peroxide in in-vitro ventral mesence-phalic neuronal culture. Since this effect was independent of theestrogen receptor, investigators hypothesized that it occurred bysequestration of cytosolic calcium (Sawada et al., 1998). Anotherstudy demonstrated that estrogen pretreatment led to attenuationof the rise of intracellular free calcium concentrations induced byglutamate (Goodman et al., 1996). Estrogen also decreases productionof reactive oxygen species by increasing expression of superoxide dis-mutase, glutathione peroxidase and glutaredoxin (Wang et al., 2001).There are several additional mechanisms by which estrogen may actto stabilize and preserve mitochondrial function in the face of varioustypes of stress. Estrogen protects mitochondrial membrane potential,prevents ATP depletion, and reduces free radical production (Simpkinset al., 2010). Transcription effects via the estrogen receptor includeincreased glucose transporter expression and increased production ofglycolytic pathway enzymes, overall leading to increased glucose utili-zation and decreased production of toxic free glutamate. Estrogen alsoincreases transcription of mitochondrial DNA andmay itself have directantioxidant effects (Simpkins et al., 2010).

Another possible mechanism by which estrogen may be protectivein PD involves α-synuclein, the pathologic protein aggregate that de-fines PD. It remains controversialwhether theseα-synuclein aggregatesthemselves are toxic to dopamine neurons leading to neuronal death,or whether sequestration of α-synuclein represents a protective de-fense mechanism by the neuron. If the former hypothesis is correct,then estrogen may also exert neuroprotective effects in idiopathic PDby preventing Lewy body formation. A single study showed that estro-gen has both anti-aggregation and fibril destabilization properties inα-synuclein specifically (Hirohata et al., 2009). Inflammation may alsoplay a role in the pathogenesis of PD, as is evidenced by microglialactivation surrounding Lewy bodies, and this is yet another possiblemechanism for estrogen neuroprotection. Estrogen appears to haveanti-inflammatory effects, including decreasing levels of cytokines andother inflammatory modulators, leukocyte CNS entry, and microgliaactivation in-vitro and in-vivo (Pozzi et al., 2006). McFarland and

estradiol

Fig. 1. Potential neuromodulatory and neuroprotective mechanisms of estradiol and related coGDNF, glial derived neurotrophic factor; ERK, extra-cellular signal regulated kinase; PI3K, phosestradiol's potential effects in the striatum and substantia nigra. Binding of ER by estradiol acti


colleagues demonstrated that a specific ERβ agonist prevented the in-crease in TNFα in peripheral blood monocytes and brain homogenateafter treatment with 6-OHDA (Olsson, 2013).

These numerous mechanisms for neuroprotection by estrogenscould lead to targeted therapies for PD and a variety of neurologicconditions. If the specificmechanisms bywhich estrogen exerts its neu-roprotective effects in PD are established, novel estrogen-like com-pounds with structural modifications may be developed to maximizeneuroprotection while minimizing unwanted systemic effects.

Interaction between caffeine and estrogen

While estrogen appears to have broad neuroprotective effects in thepathogenesis of PD, it becomesmore complicated to determine how thiseffect interacts with all of the other endogenous and exogenous factorsthat contribute to PD susceptibility. One interesting and unexpectedexample of this interaction is between estrogen and caffeine. Highercaffeine and coffee intake are associated with a reduced risk of PD inseveral large prospective and case-control studies (Ascherio, 2001;Ascherio et al., 2003). However, this risk reduction appears to be modi-fied by sex and by use of hormone replacement therapy in women.Ascherio and colleagues reported that there was a strong inverse corre-lation with coffee or caffeine intake in men. In women however, therewas a U-shaped curve, with the only significant reduction in risk with1–3 cups of coffee daily (RR = 0.6) (Ascherio, 2001). Palacios andcolleagues utilized the ACS Cancer Prevention Study II Nutrition Cohortto show that men within the highest quartile of caffeine intake com-pared to the lowest quartile had a relative PD risk of 0.43 (CI 0.26–0.71), whereas women had a non-significant reduction in relative riskto 0.61 (CI 0.34–1.09) (Palacios et al., 2012). The interplay between es-trogen and caffeine was further studied in women receiving HRT aftermenopause. Ascherio and colleagues found that PD risk was decreasedin the group with HRT use and lowest coffee intake, but that PD riskwas actually increased in the group with both HRT use and highestcaffeine intake (Ascherio et al., 2003). Caffeine therefore appears todecrease the relative risk of PD in never users of HRT, but either losesthis benefit or even increases the relative risk with concurrent estrogenexposure in users of HRT (Ascherio, 2004). There is correspondingevidence in PD animal models that estrogen interferes with the effectsof caffeine on neuroprotection. Xu and colleagues studied the effect of

mpounds. Abbreviations: ER, estrogen receptor; BDNF, brain derived neurotrophic factor;phatidylinositol 3 kinase; GSK3β, glycogen synthase kinase 3β. Schematic presentation ofvates signal cascades that ultimately decrease apoptosis of neurons.




caffeine in MPTP-treated male mice, ovariectomized females withoutestrogen replacement, and non-ovariectomized females. In males andovariectomized females, caffeine had a dose-dependent protective ef-fect on striatal dopamine levels. However, both non-ovariectomizedand estrogen-treated female mice were much less sensitive to the pro-tective effect of caffeine (Xu, 2006). Based on this epidemiologic andbasic science data, the potential neuroprotective effect of caffeine canbe negated or even reversed when endogenous or exogenous estrogenis present. Since there are currently clinical trials investigating the useof caffeine-like agents in the treatment of PD, it will be important tostratify the clinical and disease modifying effects by sex and hormonestatus. A great deal of research is underway to develop medicationsthat could prevent or slowdisease onset and progression, and sex differ-ences in response to these medications would not be surprising basedon the above literature. Although HRT has become less prevalent afterthe results of randomized trials showed increased stroke and cardiovas-cular risk, it will be useful to consider how HRT or SERM usage impactsthe efficacy of potential neuroprotective medications.

Sexual dimorphisms in dopaminergic pathways

There are sexual dimorphisms in the normal human basal ganglia,specifically within the DA system that may influence the developmentof diseases such as PD, chorea, and tics/Tourette's syndrome. Animalstudies of both rats and monkeys demonstrated that females have ahigher number of dopaminergic neurons in substantia nigra thanmales (Beyer et al., 1991). Sexual dimorphisms are also evident throughfunctional neuroimaging of the striatum in normal human subjects.While two studies showed higher [123I]β-CIT uptake in the striatumin females compared to males (Lavalaye et al., 2000), another did notshow a sex difference (van Dyck et al., 1995). In a study investigating18F fluorodopa uptakes, women were found to have higher striatal up-take than men in the caudate more than the putamen (Laakso et al.,2002). Another functional neuroimaging study using DAT bindingshowed women younger than 60 years old had 8.4% higher striatalDAT binding compared to age-matched men. However, in subjectsabove 60 years old there was no difference in DAT binding (Wonget al., 2012). Overall, these studies suggest that women and especiallyyounger women have a higher baseline number of dopamine neurons.This is relevant to PD, in which loss of dopamine neurons graduallyleads to clinical symptoms only after 80% loss (Bernheimer et al.,1973). If women have a higher reserve of dopamine neurons, this mayexplain why women develop clinical symptoms later than men.

In addition to these differences in the number of dopaminergicneurons, there are sex specific differences in molecular function of do-pamine neurons. Simunovic and colleagues showed that genes involvedin cellular homeostasis and mitochondrial function are upregulated inmales compared to females using DA neurons isolated from normalhuman postmortem brains (Simunovic et al., 2010). They hypothesizedthat these differences translate into a highermetabolic rate that acceler-ates aging and cellular demise in males. This study also investigatedthe postmortem brains of PD patients. The PD DA neurons exhibiteddysregulated gene expression profiles in both males and females, butthe gene expression profiles had little overlap between sexes. Of 36genes associated with PD pathogenesis, only 2 exhibited similardysregulation in males and females. PARK1, 6 and 7 genes were down-regulated in males compared to females, suggesting that additionalmechanisms of increased risk of disease are at play. Cantuti-Castelvetriand colleagues also investigated human dopaminergic neurons fromPD patients and controls. They determined there were sex specificdifferences independent of PD status. In females, genes for signal trans-duction and neuronal maturation were upregulated, while in males,genes for oxidative phosphorylation and PD pathogenesis-associatedgenes were upregulated. In the PD subjects, females had alterations ingene expression profiles for genes involved in protein kinase activity,proteolysis, and WNT signaling, and males had alterations in vesicle-


mediated transport, protein-binding proteins and copper-binding pro-teins (Cantuti-Castelvetri, 2007). In summary, there are sex-specificgene expression in normal DA neurons, and sex-specific dysregulationthat occurs in dopaminergic neurons in Parkinson's disease, suggestingthat the pathogenesis of the disease may differ between the sexes.

Sex chromosomes and Parkinson's disease

Despite the substantial evidence for sex steroid hormone effects onsexual dimorphisms in brain neurodegenerative diseases, it has becomeclear that hormones alone do not entirely explain these sex differences.For instance, murine cells exhibit differential gene expression profilesvery early in development, before any gonadal hormone influence(Dewing, 2003). Sex differences are also present in dopaminergicneurons grown in cultures with identical hormone environments(Raab et al., 1995; Reisert and Pilgrim, 1991). Another logical source ofdistinction betweenmales and females is genetics, and in fact it does ap-pear that both the X and Y chromosomes contribute to these differencesindependently.

Much of this research focused on genes unique to a single sex, andthis has led to investigation of the SRY region of the Y chromosome.SRY encodes a transcription factor that is responsible for gonadal differ-entiation and therefore sex steroid hormone production. In male mice,SRY is expressed in the substantia nigra, and was found to localize ex-clusively in TH-positive neurons (Dewing, 2006). Czech and colleaguesreported that SRY is expressed in substantia nigra pars compacta andreticulata, and ventral tegmental area of humanmales, and that expres-sion co-localized with a subset of 43% of TH-positive neurons (Czechet al., 2012).

Researchers have proposed that SRY is an important positive regula-tor of dopamine synthesis andmetabolism. SRY expression is associatedwith increased monoamine oxidase-A (MAO-A), DOPA decarboxylase,dopamine β-hydroxylase, D2 receptor and tyrosine hydroxylase (TH)levels (Tao et al., 2011; Wu et al., 2009). ERβ levels are either increasedor decreased with SRY (Wu et al., 2009). From the above results, itremains unclear whether SRY has an overall pro- or anti-dopaminergiceffect. When SRY is overexpressed, there is increased expression ofMAO-A, which in isolation would lead to decreased dopamine levelsdue to increased metabolism. It is important to note that the MAO-Agene is located on the X chromosome, and the gene core promotercontains a SRY-binding site. This was the first X-linked gene to demon-strate regulation by SRY, and introduced a novel mechanism forsexual dimorphisms in normal and disease states. There also appears tobe an SRY-binding site in the promoter region of the ERβ gene.SRY-overexpressed cells also demonstrated increased resistance to hy-drogen peroxide-induced cytotoxicity through unclear mechanisms(Tao et al., 2011). On the other hand, SRY downregulation (via antisenseoligodeoxynucleotides), led to decreased TH expression, and further-more led to decreased spontaneous movement on the contralateralside when unilateral injections into substantia nigra were performed(Dewing, 2006). This phenotypic outcome suggests that SRY overallhas a pro-dopaminergic effect. Furthermore, SRYmay promote the initialdevelopment of the dopamine neuron population. Czech and colleaguesnoted that as neuronal precursor cells differentiated into dopamineneurons, a rise in SRY preceded a rise in TH. Further evidence that THexpression is under control of SRY was that SRY knockdown resulted indecreased TH expression, and that SRY was able to activate the TH pro-moter (Czech et al., 2012). The Y chromosome contains a number ofgenes in addition to the SRY region, which are responsible for sex deter-mination. Studies in mouse embryo cells to determine the effect of theY chromosome in the absence of testis development and sex steroid hor-mone production dissociated the SRY region from the Y chromosome(Carruth et al., 2002). In this study, cells that were XY but lacked SRYhad higher levels of TH-positive neurons than cells that were XX. Thissuggests that there are mechanisms other than direct SRY-mediatedupregulation of TH expression that are unknown.




The X chromosome copy number is another potential variable un-derlying sexual dimorphisms. Chen and colleagues reported that thecomplement of X chromosomes impacts gene expression in the stria-tum independently of gonadal sex (Chen et al., 2009). The experimentsused mouse models that separated sex chromosome complement fromgonadal sex. XX mice had increased levels of prodynorphin (Pdyn) inthe striatum compared to XY of the same gonadal sex or XO mice,which suggests that the number of X chromosomes is the key variableindependent of the presence or absence of a Y chromosome. This mayrelate to PD because it has been shown that genetic variation in the Xchromosome associates with PD susceptibility, though no specificPD-related genes have been identified that are differentially expressedin this X chromosome-dependent manner (Pankratz et al., 2003). ThisX-dependent mechanism of gene expression has been called the“hemizygous exposure” effect, and may be due to genes that escape Xinactivation. Therefore, in addition to sex steroid hormone effects, boththe X and Y chromosomes individually may have distinct contributionsto sex differences in the pathogenesis and clinical characteristics of PD.

Huntington's disease and sex

Huntington's disease is a neurodegenerative disease caused by apolyglutamate triplet repeat expansion (CAG) on chromosome 4. It isa hyperkinetic disorder characterized by chorea, tremor, dystonia, andprominent neuropsychiatric and cognitive changes. As it is inheritedin an autosomal dominant fashion, there are both equal penetrancein individuals and prevalence in the population in men and women.However, animal models of Huntington's disease as well as from epide-miologic cohorts suggest that sex may account for a portion of thevariability in the disease between males and females. Similar to PD,there is some evidence that estrogen has neuroprotective effects onthe mechanisms underlying Huntington's disease development, specif-ically oxidative stress and glutamate excitotoxicity (Weaver et al.,1997). Dorner and colleagues reported that striatal ascorbate releaseupon behavioral activation, a marker of functional reserve in the KImouse model of Huntington's disease, was increased in female micecompared tomales.While estrogen has been shown tomodulate ascor-bate release in other settings of oxidative stress such as ischemia, thisspecific effect has not been studied in Huntington's disease modelsspecifically (Dorner et al., 2007). There are 2 additional reports of17β-estradiol protecting against other markers of lipid peroxidationand oxidative stress in models of Huntington's disease (Heron andDaya, 2000; Tunez et al., 2006). One study by Bode and colleaguesexamined endogenous 17β-estradiol levels in the tgHD mouse model,in which females did not display significant motor dysfunction inthe accelerod test during the first 14 months of life. There were signifi-cant correlations between 17β-estradiol levels and total number ofDARPP32+ medium spiny neurons (MSN) as well as total striatal cellvolume. ERα and ERβ were both expressed on DARPP32+ MSNs, thusthey hypothesized that estrogen, through receptor-mediated effects,leads to neuroprotection that translates to less severe motor dysfunc-tion in females with Huntington's disease (Bode et al., 2008).

This scientific evidence suggesting a protective effect of estrogen inHuntington's disease is preliminary, and the epidemiologic evidenceis contradictory. There is conflicting information with some studiesthat suggest female sex is detrimental while others suggest that it isprotective. In a large European cohort, women had a more severe dis-ease phenotype and faster progression despite no difference in age ofonset (Zielonka et al., 2013). Other studies have found that womenhad a later age of onset and longer course (Foroud et al., 1999). SinceHuntington's disease has a clear inheritance pattern and a youngerage of onset than PD, it is difficult to correlate age at onset and earlyclinical characteristics with lifetime estrogen exposure, and it wouldbe rare for patients to have been on hormone replacement therapy. Insummary, sex differences likely account for a small portion of the


phenotypic variance in Huntington's disease and the multifactorialneuroprotective effects of estrogen may extend to this disease.

Chorea gravidarum and Sydenham's disease

If estrogen possesses pro-dopaminergic properties as described abovein PD, it would logically follow that estrogen may exacerbate conditionsmediated by hyper-dopaminergic states. This, while oversimplified, de-scribes the hyperkinetic movement disorders, including chorea. Choreais a key symptom of Huntington's disease as discussed in the prior sec-tion, and some studies indeed have shown thatwomenhavemore severeclinical symptoms including chorea (Zielonka et al., 2013). Anotherkey example is Sydenham's chorea, which becomes persistent morefrequently in females, and can recur during pregnancy or estrogenexposure (Fahn et al., 2011). Choreic movements during pregnancy, orchorea gravidarum, may represent a variant of Sydenham's disease, or itmay be the first sign of systemic lupus erythematosus or the relatedantiphospholipid syndrome. Further research will be necessary to deter-mine estrogen's role in chorea and its underlyingmechanisms of action inthe basal ganglia, so the data could be applied therapeutically.

Tics and Tourette's syndrome

Tics and Tourette's syndrome (TS) are thought to be caused bydopamine signaling dysfunction, in addition to other neurotransmitterabnormalities within the cortico-striatal-thalamocortical circuits. TScriteria include both motor and vocal tics. It is much more common inboys than girls with a prevalence ratio of approximately 4:1, despite aproposed autosomal dominant mode of transmission (Bortolato et al.,2013; Jankovic and Kurlan, 2011). There are several possible contribut-ing factors to this sex-dependent susceptibility. First, there are baselinesexual dimorphisms in the basal ganglia pathways thought to beinvolved in tics and TS. One important structure in TS is the ventral stri-atum, which receives input from the sexually dimorphic amygdala andbednucleus of the stria terminalis. Arginine vasopressin (AVP)mediatesthis pathway, and AVP levels are higher in males at baseline, aredecreased after castration, and restored by exogenous testosteronetherapy (Peterson et al., 1992). Therefore, structural differences thatoccur during brain development may be influenced later in life bygonadal hormones.

Sex steroid hormones also influence the severity of tics in bothfemales and males, and may additionally play a role in disease patho-genesis. It is well known that tics tend to begin around the age ofadrenarche, and often improve at puberty and even more in adulthood.Anabolic steroids worsen tic severity in males (Leckman and Scahill,1990). Schwabe and colleagues found that 26% of 47 womenexperienced increased tic severity during the estrogenic phase ofthe menstrual cycle (Schwabe and Konkol, 1992). In another study,however, no correlation was found between tic severity and estrogenor progesterone levels in 8 women (Kompoliti et al., 2001).

A recent article by Bortolate and colleagues summarized the roleof neuro-steroids in TS. Currently, there are clinical studies of5α-reductase inhibitors in the treatment of TS. Briefly, 5α-reducataseinhibitors exert anti-dopaminergic effects that appear to be largelymediated through D1 receptors (these receptors are the main subtypeimplicated in TS). An open label trial of finasteride, a common5α-reductase inhibitor, was successful in significantly decreasing ticseverity and compulsive symptoms in adult men (Muroni et al., 2011).

Conclusions

In conclusion, sex differences play an important role in the suscepti-bility to, and pathogenesis of, various movement disorders. Sexualdimorphisms in structure and function appear during development, likelydue to effects of both sex steroid hormones and sex chromosomes. Sexsteroid hormones furthermore appear to influence the dopaminergic




system in both healthy and disease states. Estrogen exerts a pro-dopaminergic effect, which may both decrease the risk of PD in women,as well as predispose to hyperkinetic conditions such as chorea. Bystudying the mechanisms of action of estrogen in the basal ganglia, therole of estrogen in various movement disorders will become clearer. Itis becoming increasingly recognized that estrogen may exert neuropro-tective effects in many neurologic disease processes, including PD andHuntington's disease. We reviewed the literature on neuroprotective ef-fects of estrogen and related hormones in neurotoxin-mediated animalmodels of PD. There is a high quantity and consistency of evidence thatdescribes specific estrogen compounds, such as 17β-estradiol, as neuro-protective. The selective estrogen receptor modulators are also verypromising neuroprotective agents and deserve further study. SERMsmay be chemically modified to optimize neuroprotection and minimizethe side effects and risk of cardiovascular disease that have been reportedwith HRT in post-menopausal women. This will require further elucida-tion of themechanisms underlying estrogen's neuroprotective effects, in-cluding estrogen receptor-dependent signal cascades and non-receptor-dependent effects. The field of neurodegenerative disease and especiallyPD are in great need of agents that can prevent or slow disease progres-sion. Researchers have discovered clinical and biochemical markers ofdisease that identify patients-at-risk, even before onset of motor symp-toms, during which time neuroprotective agents would be most likelyto succeed. In summary, sex steroid hormones and sex chromosomesplay a role in various movement disorders through effects on basalganglia networks and the dopaminergic system in particular. Furtherexploration of these sex differences will be integral to understandinghow these disorders develop and present clinically, and ultimately, todevelop new therapies in the field of movement disorders.

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Sex differences in Parkinson's disease and other movement disorders