Thérèse Di Paolo

Introduction: Parkinson’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. Methods: Mice 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. Results: Raloxifene 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. Conclusion: Raloxifene and progesterone treatment was neuroprotective without excessive uterine stimulation in OVX mice supporting repurposing of these drugs for PD and their high translational value.

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.

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 the progressive loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc), leading to the appearance of debilitating motor symptoms, in addition to nonmotor symptoms.^1,2 This neurodegenerative disorder is incurable, and although some motor symptoms can be alleviated by the administration of the DA metabolic precursor levodopa, such pharmacotherapy eventually leads to adverse side effects in the form of dyskinesias, leaving very limited options for alternative treatments.^{3 – 6} As the second most common neurodegenerative disease next to Alzheimer’s disease (AD), it is a burden on healthcare services worldwide, especially with the rapidly increasing aging population.⁷ For this reason, research efforts are being made to find alternative ways to detect PD, alleviate its symptoms, slow its progression, and find a cure.

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-phenyl-1,2,3,6-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.

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.