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 etiopathogenesis of Parkinson's Disease (PD) remain poorly understood, particularly the roles of aging and the gut-brain axis. This study investigated the impact of aging on the development of PD hallmarks, including neurodegeneration and inflammation, in both the central (CNS) and enteric (ENS) nervous system of mice following exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Young (2-4 months) and adult (7-12 months) mice were treated with either saline or MPTP (four intraperitoneal injections of 8 mg/kg at 2-hour intervals). Postmortem inflammatory and neuronal endpoints were compared in both the nigrostriatal pathway and the myenteric plexus. While age did not alter the MPTP-induced reduction in TH-positive cells in the striatum and substantia nigra pars compacta (SNpc), we observed a greater sensitivity of enteric DAergic neurons to MPTP neurotoxicity with age. Notably, MPTP treatment elicited a more prominent inflammatory response in the SNpc and the myenteric plexus in older animals, as assessed with Iba1 and GFAP immunofluorescence on brain sections. We also observed enteric and central inflammation, an increase in oxidative stress in the SNpc measured with Nrf2, and a loss of enteric DAergic neurons with aging, comparable to what is observed in young mice treated with MPTP. The enhanced vulnerability of the ENS is consistent with the observation that intestinal symptoms precede motor symptoms in PD, suggesting that immunosenescence in the gastrointestinal tract contributes to the early development and progression of PD.

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.