BACKGROUND:Exposure to environmental agents, including viral infections, may increase Parkinson's disease (PD) susceptibility, especially in males, but the neurodegenerative risk extent of COVID-19 remains uncertain. OBJECTIVES:We investigated the plausible link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and PD susceptibility across sexes. METHODS:Mice overexpressing the human angiotensin-converting enzyme 2 receptor (K18-hACE2) were exposed to SARS-CoV-2 or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) doses. This was followed by a two-hit experiment in which mice received a moderate MPTP dose and SARS-CoV-2 11 days post-MPTP. Striatal viral titer was measured 4 days postinfection (dpi). After 14 dpi, striatal dopamine and its metabolites (3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid), nigrostriatal degeneration, and glial responses in males and females were compared. RESULTS:Only in males, SARS-CoV-2 resulted in progressive dopamine metabolic dysregulation by day 21. Coexposed females showed less weight loss than males. Coexposed males showed significant nigrostriatal degeneration, together with robust nigral astrocytic and microglial reactivity exceeding individual effects. In females, MPTP and/or SARS-CoV-2 had minimal effects on dopamine and its metabolism, degeneration, and microglial reactivity, whereas coexposure was associated with significant nigral astrocytic reactivity. In coexposed males, striatal microglia showed enhanced territorial spacing, whereas in females, they became more clustered, possibly because of an enrichment of cells with larger soma and retracted processes. In males, single or dual exposure stressed degenerating dopamine neurons to shrink and dilate their Golgi bodies, more prominently in the coexposed group. CONCLUSIONS:This study reports the sex-dependent COVID-19 effects on mice prodromal PD with a differential glial contribution, supporting glial- and sex-based medical approaches. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons and accumulation of α-synuclein (α-syn)-containing Lewy bodies in the substantia nigra (SN) pars compacta. Mutations in the gene coding for the protein parkin cause a form of autosomal recessive juvenile parkinsonism, but its role in idiopathic PD is poorly understood. Here, to investigate parkin changes in the SN in PD, we established a clinicopathology research platform comparing PD patients (n = 24) with Controls (n = 21). We first confirmed the massive loss of dopamine (DA) levels (−96%) in the putamen of PD patients, using HPLC/electrochemistry. Higher levels of phosphorylated α-syn (αsynP129) (23-fold) were observed in the SN of PD patients by Western immunoblotting. In formic acid extracts, an increase in the insoluble oligomeric form of parkin migrating at 260 kDa was observed (+ 49%) in the SN of PD patients, along with lower levels of the 55 kDa monomeric form (−47%). These changes in parkin were specific for the SN, and not observed in the putamen, parietal cortex and cerebellum. High molecular weight parkin correlated with αsynP129 levels and dopamine loss and was more prominently found in PD patients with levodopa-induced dyskinesias. Additional studies in animal models suggest that the aggregation of parkin is not a direct consequence of dopaminergic depletion or αsyn overproduction, but a component of PD cellular pathophysiology. Taken together, the results reported herein show that, beside dopamine loss and increased αsynP129, neurodegeneration in idiopathic PD is associated with a conversion of parkin into an insoluble high molecular weight form in the SN.

Diagnosis of Parkinson’s disease (PD) is currently made following clinical observation of motor symptoms. By the time these symptoms manifest, around 50% of dopamine neurons are lost in the substantia nigra pars compacta, limiting the possibility of implementing potential neuroprotective treatments that could delay the progression of the disease. Non-motor symptoms, such as vision problems, occur much earlier along the progression of the disease. If altered functioning of the retina causes these vision problems, various techniques could be implemented to detect retinal changes, therefore providing early biomarkers for PD. The aim of this project is to determine potential biomarkers for PD via the retina by using electroretinography (ERG) and pupillometry. In vivo measurements were performed on four non-human primates, before and after they were rendered parkinsonian by administration of 1-méthyl-4-phényl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces degeneration of dopamine neurons. Post-mortem retinal analyses were compared against the retina of four additional control monkeys. ERG results showed a significant increase in photopic b-wave implicit time and reduced oscillatory potential (OP) amplitudes in both photopic and scotopic conditions following MPTP administration. These OP amplitudes were restored following L-dopa administration. Analysis of the post-illumination pupillary response showed a consistently larger pupil diameter postMPTP. Post-mortem examination reveals a significant thinning of the outer nuclear retinal layer. A reduced number of tyrosine hydroxylase and melanopsin containing cells is also found in MPTP-intoxicated monkeys. Altogether, these results indicate that MPTP-induced degeneration of dopamine neurons leads to functional changes to the retina detectable by ERG and pupillometry, and that these changes could be attributed to cellular alterations in the retina as observed post-mortem. This study provides evidence for potential retinal biomarkers that could be used as an earlier or more accurate means of diagnosing PD.

Parkinson's disease (PD) diagnosis is currently made by clinical observation of motor symptoms when around 50% of dopamine neurons in the substantia nigra pars compacta are already lost. Non-motor symptoms, such as vision problems, occur earlier during disease progression and could be caused by altered retinal functioning. Various techniques exist to detect retinal alterations and, therefore, could provide biomarkers for earlier diagnosis of PD. The aim of this project is to determine potential retinal biomarkers for PD by using electroretinography (ERG) and pupillometry. In vivo measurements were performed on four non-human primates, before and after they were rendered parkinsonian by administration of 1-méthyl-4-phényl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces degeneration of dopamine neurons. ERG results showed a significant increase in photopic b-wave implicit time and reduced oscillatory potential (OP) amplitudes in both photopic and scotopic conditions following MPTP administration. The post-illumination pupillary response showed a consistently larger pupil diameter post-MPTP. Post-mortem examination revealed a significant thinning of the outer nuclear retinal layer. Tyrosine hydroxylase and melanopsin-containing cells were reduced in MPTP-intoxicated monkeys. Altogether, these results indicate that MPTP intoxication leads to functional retinal changes detectable by ERG and pupillometry, possibly attributed to cellular alterations.

IntroductionParkinson’s disease (PD) main pathological feature involves degeneration of dopamine (DA) neurons in the brain substantia nigra (SN). Female gonadal steroids are shown to be neuroprotective in animal models of PD and tested mainly in male and less in female animals. Since most women with PD are in menopause the present study tested ovariectomized (OVX) female mice as a model of the hormonal condition of menopause. This study sought the neuroprotective effect of the selective estrogen receptor modulator (SERM) raloxifene and progesterone alone and in combination to protect DA neurons in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned mice as a model of PD.MethodsMice were treated with vehicle, raloxifene (2.5 mg/kg, b.i.d., subcutaneous), progesterone (1 μg, b.i.d., subcutaneous) and their combination for 10 days and administered MPTP (5.5 mg/kg, intraperitoneal) or saline on the 5th day; brains and uteri were collected thereafter.ResultsRaloxifene treatment led to only small increases in uterine weights less than an average of intact mice uterine weights and no effect of progesterone. OVX MPTP-lesioned female mice showed a loss of striatal DA and metabolites content similarly prevented by treatments with raloxifene, progesterone and their combination. By contrast, striatal serotonin and metabolite remained unchanged. Striatal glial fibrillary acidic protein (GFAP), an astrogliosis marker, levels were elevated in MPTP-lesioned mice and this was similarly prevented with the hormonal treatment alone or in combination.ConclusionRaloxifene and progesterone treatment was neuroprotective without excessive uterine stimulation in OVX mice supporting repurposing of these drugs for PD and their high translational value.

Presynaptic accumulation of misfolded α-synuclein (α-syn) and altered synaptic transmission are considered early events in the pathogenesis of Parkinson’s disease (PD), suggesting a potential causal link between these two events. However, the mechanisms by which α-syn aggregation induces synaptic dysfunction and the subsequent progressive neurodegeneration remain elusive. In the present study we leveraged the high temporal resolution of the Light-Inducible Protein Aggregation (LIPA) system in vivo and in human dopaminergic neurons to explore the early sequence of α-syn-induced pathological events leading to synaptopathy. We observed that nigrostriatal axonal transport and presynaptic accumulation of α-syn aggregates altered the activity of different neuronal populations in the mouse striatum. The results of histological and metabolite analyses show that presynaptic accumulation of α-syn induced a shift in the activation pattern of D1- and D2-expressing striatal medium spiny neurons, caused an increase in the size and density of dopaminergic synapses, and disrupted striatal dopamine signaling. Altogether, our findings reveal that the accumulation of α-syn in dopaminergic terminals triggered early presynaptic impairments, which subsequently altered striatal neuronal activity. Our study provides new insights into the molecular mechanisms underlying early synaptopathy in PD.

Significance:Parkinson's disease (PD) is diagnosed when 50% neurodegeneration has occurred. The retina could provide biomarkers that would allow for earlier diagnosis. Retinal spectroscopy is a technique that could be used to find such biomarkers. Aim:We aimed to find new diagnostic biomarkers for PD following detailed spectral examinations of the retina. Approach:The newly developed Zilia Ocular device was used to perform spectrometric scans of the optic nerve head (ONH) and the retina of four cynomolgus monkeys (Macaca fascicularis) before and after the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin used to produce the gold-standard animal model of PD. From the spectrometric data, the blood oximetry was calculated, and the diffuse reflectance spectra (DRS) were analyzed to find variations between the two experimental conditions. Post-mortem analyses were also performed on the retina of the four parkinsonian monkeys and four additional control animals. Results:The analysis of the DRS indicated a lower slope between the 480- and 525-nm wavelengths in both the ONH and the retina. Post-mortem measurements of the retinal layer thicknesses showed that the outer nuclear layer was significantly thinner in MPTP-intoxicated monkeys, compared with controls. Altogether, these results indicate that MPTP altered the optical properties of the ONH and the retina and show that these variations might be explained by MPTP-induced structural changes in the eye fundus, as observed post-mortem. Conclusions:Overall, our results indicate that spectroscopy could be used as a noninvasive method to detect changes in the retina that occur in PD and that such changes could represent retinal biomarkers for improved diagnosis.

BACKGROUND:Pregnenolone is the first neurosteroid synthesized from cholesterol in the brain. Previous studies showed that it reduces the development of levodopa (L-dopa)-induced dyskinesias (LIDs) in rat models of Parkinson's disease (PD). OBJECTIVE:To examine whether pregnenolone mitigates established LIDs in a non-human primate model. METHODS:Ovariectomized female macaques, modeling the postmenopausal hormonal status of most women with PD, were lesioned with MPTP and treated with L-dopa to induce LIDs. Pregnenolone was administered subcutaneously (SC) at 6 or 18 mg/kg or orally (36 mg/kg). RESULTS:Pregnenolone reduced established LIDs in MPTP-lesioned monkeys while preserving L-dopa's antiparkinsonian effects. The antidyskinetic effect was dose-dependent, with the greatest reduction observed at 18 mg/kg SC, followed by 6 mg/kg SC, and a lesser effect at 36 mg/kg orally, likely due to first-pass metabolism. CONCLUSIONS:Pregnenolone reduces established LIDs in parkinsonian monkeys and may represent a safe, novel therapeutic candidate for dyskinesia treatment in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson’s disease (PD) is characterized by motor symptoms due to loss of brain dopamine and non-motor symptoms, including gastrointestinal disorders. Although there is no cure for PD, symptomatic treatments are available. L-Dopa is the gold standard PD therapy, but most patients develop dyskinesias (LID), which are challenging to manage. Amantadine is recognized as the most effective drug for LID, but its adverse effects limit the use in patients. Here we review how 5α-reductase inhibitors (5ARIs), drugs used to treat benign prostatic hyperplasia and alopecia, exhibit beneficial effects in PD animal models. 5ARIs show neuroprotective properties in brain and gut dopaminergic systems, and reduce dyskinesias in rodent model of PD. Additionally, the 5ARI finasteride dampened dopaminergic-induced drug gambling in PD patients. Neuroprotection and antidyskinetic activities of 5ARIs in animal models of PD suggest their potential repurposing in men with PD to address gut dysfunction, protect brain DA and inhibit dyskinesias.

Background: Parkinson's disease (PD) chronic L-Dopa treatment often triggers motor complications, such as L-Dopa-induced dyskinesias (LID). LID are reported to be associated with abnormal glutamatergic activity between the striatum and primary motor cortex (M1), resulting in M1 hyperactivation. Beneficial noninvasive brain stimulation (NIBS) paradigms were reported to normalize glutamatergic activity. The objective of the present study was thus to set up a NIBS paradigm in parkinsonian monkeys to investigate motor behavior under basal conditions and with L-Dopa treatment-inducing dyskinesias. Methods: Motor behavior was investigated in five 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) dyskinetic female Macaca fascicularis monkey models of PD, allowing us to monitor the administration of NIBS and drugs. NIBS used were inhibitory protocols, that is, cathodal transcranial direct current stimulation (c-tDCS) and continuous theta- burst stimulation (cTBS). A procedure of three weeks was developed to progressively acclimate animals to the experimental conditions, equipment and noise of c-tDCS and cTBS before stimulating them with either vehicle or L-Dopa. Results: One session of c-tDCS with L-Dopa yielded no effect, whereas five sessions briefly reduced LID but decreased the duration of L-Dopa anti-PD effects. cTBS alone improved (decreased) parkinsonian scores as compared to sham stimulation or vehicle alone. Two sessions of cTBS with L-Dopa decreased LID without affecting L-Dopa anti-PD effects. Conclusion: This is the first study testing c-tDCS and cTBS on the motor behavior of MPTP dyskinetic monkeys. As compared to medicated patients, MPTP monkeys offer the opportunity to evaluate NIBS after-effects in drug-free and LID conditions, which are critical in the search for new PD treatment.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Inflammation has been observed in both the idiopathic and familial forms of PD. Importantly, PD is reported more often in men than in women, men having at least 1.5- fold higher risk to develop PD than women. This review summarizes the impact of biological sex and sex hormones on the neuroimmune contributions to PD and its investigation in animal models of PD. Innate and peripheral immune systems participate in the brain neuroinflammation of PD patients and is reproduced in neurotoxin, genetic and α-synuclein based models of PD. Microglia and astrocytes are the main cells of the innate immune system in the central nervous system and are the first to react to restore homeostasis in the brain. Analysis of serum immunoprofiles in female and male control and PD patients show that a great proportion of these markers differ between males and females. The relationship between cerebrospinal fluid inflammatory markers and PD clinical characteristics or PD biomarkers shows sex differences. Conversely, in animal models of PD, sex differences in inflammation are well documented and the beneficial effects of endogenous and exogenous estrogenic modulation in inflammation have been reported. Targeting neuroinflammation in PD is an emerging therapeutic option but gonadal drugs have not yet been investigated in this respect, thus offering new opportunities for sex specific treatments.

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stim-ulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) pre-vented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.

The greater prevalence and incidence of Parkinson's disease (PD) in men suggest a beneficial effect of sex hormones. Neuroactive steroids have neuroprotective activities thus offering interesting option for disease-modifying therapy for PD. Neuroactive steroids are also neuromodulators of neurotransmitter systems and may thus help to control PD symptoms and side effect of dopamine medication. Here, we review the effect on sex hormones (estrogen, androgen, progesterone and its metabolites) as well as androstenediol, pregnenolone and dehydroepiandrosterone) in human studies and in animal models of PD. The effect of neuroactive steroids is reviewed by considering sex and hormonal status to help identify specifically for women and men with PD what might be a preventive approach or a symptomatic treatment. PD is a complex disease and the pathogenesis likely involves multiple cellular processes. Thus it might be useful to target different cellular mechanisms that contribute to neuronal loss and neuroactive steroids provide therapeutics options as they have multiple mechanisms of action.

Parkinson’s disease (PD) is characterized by neurodegeneration and neuroinflammation. PD prevalence and incidence are higher in men than in women and modulation of gonadal hormones could have an impact on the disease course. This was investigated in male and female gonadectomized (GDX) and SHAM operated (SHAM) mice. Dutasteride (DUT), a 5α-reductase inhibitor, was administered to these mice for 10 days to modulate their gonadal sex hormones. On the fifth day of DUT treatment, mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. We have previously shown in these mice the toxic effect of MPTP in SHAM and GDX males and in GDX females on dopamine markers and astrogliosis whereas SHAM females were protected by their female sex hormones. In SHAM males, DUT protected against MPTP toxicity. In the present study, microglial density and the number of doublets, representative of a microglial proliferation, were increased by the MPTP lesion only in male mice and prevented by DUT in SHAM males. A three-dimensional morphological microglial analysis showed that MPTP changed microglial morphology from quiescent to activated only in male mice and was not prevented by DUT. In conclusion, microgliosis can be modulated by sex hormone-dependent and independent factors in a mice model of PD.

The mutation and overexpression of the alpha-synuclein protein (αSyn), described as synucleinopathy, is associated with Parkinson's disease (PD)-like pathologies. A higher prevalence of PD is documented for men versus women, suggesting female hormones' implication in slowing PD progression. The nigrostriatal dopamine (DA) neurons in rodent males are more vulnerable to toxins than those in females. The effect of biological sex on synucleinopathy remains poorly described and was investigated using mice knocked out for murine αSyn (SNCA-/-) and also overexpressing human αSyn (SNCA-OVX) compared to wildtype (WT) mice. All the mice showed decreased locomotor activity with age, and more abruptly in the male than in the female SNCA-OVX mice; anxiety-like behavior increased with age. The SNCA-OVX mice had an age-dependent accumulation of αSyn. Older age was associated with the loss of nigral DA neurons and decreased striatal DA contents. The astrogliosis, microgliosis, and cytokine concentrations increased with aging. More abrupt nigrostriatal DA decreases and increased microgliosis were observed in the male SNCA-OVX mice. Human αSyn overexpression and murine αSyn knockout resulted in behavioral dysfunctions, while only human αSyn overexpression was toxic to DA neurons. At 18 months, neuroprotection was lost in the female SNCA-OVX mice, with a likely loss of estrus cycles. In conclusion, sex-dependent αSyn toxicity was observed, affecting the male mice more significantly.

N-methyl-D-aspartate (NMDA) receptors have been implicated in L-Dopa-induced dyskinesias (LID) in Parkinson’s disease patients, but the use of antagonists that directly inhibit this receptor is associated with severe side effects. L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. The 7-Cl-KYNA has limited ability to cross the blood–brain barrier, whereas AV-101 readily accesses the brain. We investigated if AV-101 reduces LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys while maintaining the antiparkinsonian activity of L-Dopa. A first pilot study using three dyskinetic MPTP monkeys showed that acute AV-101 treatment (250 and 450 mg/kg) reduced LID and maintained the antiparkinsonian activity of L-Dopa. The main study using six additional dyskinetic MPTP monkeys showed that repeated AV-101 treatment (250 mg/kg, b.i.d. for 4 consecutive days) maintained their L-Dopa antiparkinsonian response. We measured significantly less LID when AV-101 was combined with L-Dopa treatment. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects.

24S-hydroxycholesterol (i.e., cerebrosterol, 24S-OH-Chol) is the main form of cholesterol elimination from the brain. Liquid chromatography-tandem mass spectrometry methods were developed for the quantification of the total and unesterified/unbound fractions of 24S-OH-Chol, its monosulfate, monoglucuronide, and diconjugate derivatives (24S-OH-Chol-3sulfate [3S], 24S-OH-Chol-24glucuronide [24G] and 24S-OH-Chol-3S, 24G, respectively) in human plasma. Linearity, precision, accuracy, and extraction recovery were validated within the typical physiological and pathological ranges of concentrations for each compound. The lower limit of quantifications was 2.00, 0.33, 0.26, and 0.74 ng/ml for 24S-OH-Chol, 24S-OH-Chol-24G, 24S-OH-Chol-3S, and 24-OH-Chol-3S, 24G, respectively. Extraction recovery values in total and unbound plasma fractions were also analyzed in murine and monkey plasma and varied from 73% in mouse to 113% in cynomolgus monkey. The methods could rapidly (less than 7 min) quantify individual compounds with high sensitivity, accuracy (bias ≤15%), and reproducibility (coefficient of variation [CV] ≤ 17%). Their clinical applications were validated by measuring levels of the 4 compounds in samples from 20 noncholestatic donors, 5 cholestatic patients suffering from primary biliary cirrhosis, and 10 patients suffering from biliary stenosis. Results highlight the abundance of 24S-OH-Chol in the total fraction and the abundance of 24S-OH-Chol-3S and 24G in the unbound ones. While the latter strongly accumulate in plasma fractions of cholestatic patients, levels of 24S-OH-Chol remained similar to those of healthy donors. Our results indicate that this approach is suitable for monitoring cerebrosterol and its conjugates in large-scale clinical studies.

Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.

Accumulating epidemiological and clinical studies support a greater prevalence and incidence of Parkinson's disease (PD) in men than women, suggesting a potential contribution of sex hormones. Sex steroids can affect the brain (neuroactive steroids) and can also be synthesized in the brain (neurosteroids). Findings in PD patients and animal models of PD support a beneficial role of estrogen and progesterone, whereas androgens have not consistently shown beneficial or a deleterious effects. Estrogen and progesterone provide treatment options to be optimized including which estrogen/progesterone, the dose, duration and time of initiation of treatment. Drug modulating steroid synthetic pathways, pro-drugs, steroid precursors, brain selective estrogens, long-lasting formulations are promising treatments for precision hormonal therapy for PD in women and men, avoiding feminizing effects.

Beneficial effects of estrogens have been reported in Parkinson's disease (PD) for many years. We previously reported their neuroprotective and anti-inflammatory potentials in the enteric nervous system of the intestine, a region possibly affected during the early stages of the disease according to Braak's hypothesis. Three different estrogen receptors have been characterized to date: the estrogen receptor alpha (ER alpha), the estrogen receptor beta (ER beta) and the G protein coupled estrogen receptor 1 (GPER1). The aim of the present study was to decipher the individual contribution of each estrogen receptor to the therapeutic properties of 17 beta-estradiol (E2) in the myenteric plexus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Different agonists, 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT; ER alpha), 2,3-bis(4-hydroxyphenyl)-propioni-trile (DPN; ER beta), G1 (GPER1), and antagonists, ICI 182,780 (ER alpha and ER beta), G15 (GPER1), were used to analyze the involvement of each receptor. We confirmed that G1 protects dopamine (DA) neurons to a similar extent as E2. An anti-inflammatory effect on proinflammatory macrophages and cultured human monocytes was also demonstrated with E2 and G1. The effects of PPT and DPN were less potent than G1 with only a partial neu-roprotection of DA neurons by PPT and a partial reduction of interleukin (IL)-1 beta production in monocytes by PPT and DPN. Overall, the present results indicate that the positive outcomes of estrogens are mainly through activation of GPER1. Therefore, this suggests that targeting GPER1 could be a promising approach for future estrogen-based hormone therapies during early PD.