Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson's disease

Abstract

Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10 days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5 days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro‐inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8 mg kg‐1 progesterone administered after MPTP. In the brain of MPTP mice, brain‐derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection. In the myenteric plexus, increased BDNF levels compared to controls were measured in MPTP mice treated with 8 mg kg‐1 progesterone started post MPTP, whereas GFAP levels remained unchanged. In conclusion, the results obtained in the present study show neuroprotective and anti‐inflammatory effects of progesterone in the myenteric plexus of MPTP mice that are similar to our previous findings in the brain. Progesterone is non‐feminising and could be used for both men and women in the pre‐symptomatic stages of the disease.

Interplay of gut microbiota and oxidative stress: Perspective on neurodegeneration and neuroprotection

“…Oestrogenic molecules also affects differentiation and myelination in oligodendrocytes [221] . Recent report also showed that even progesterone treatment in MPTP parkinsonian mouse model showed neuroprotective, anti-inflammatory and immune-modulatory effects, but whether the neuroprotective role begins in gut or brain is still unknown [222] .…”

Unmet Needs of Women Living with Parkinson's Disease: Gaps and Controversies

“…In preclinical studies, estrogen has been shown to have antiapoptotic and antioxidant effects, 24 in addition to inhibiting α‐synuclein fibril stabilization and aggregation 25 . Several studies have demonstrated that higher total lifetime estrogen exposure may be associated with a decreased risk of PD in women, 26‐29 although some other studies have been inconclusive 24,30‐34 …”

“…25 Several studies have demonstrated that higher total lifetime estrogen exposure may be associated with a decreased risk of PD in women, [26][27][28][29] although some other studies have been inconclusive. 24,[30][31][32][33][34] The timing of estrogen exposure and association with sexual hormones may be critical factors 35 : it has been shown that postmenopausal estrogen-only treatment among women with hysterectomy may increase the risk of PD compared to no increased risk when women experience natural menopause and receive usual treatment with a combination of estrogen and progesterone. 36 A recent retrospective analysis showed that greater duration of HRT was associated with reduced risk of neurodegenerative disease, including PD.…”

Neuroactive steroids and the new decade

“…These events could be related to the homeostatic and protective actions of steroids in neural cells, as well as to the manifestation of sex differences in neurodegenerative disorders . The involvement of progesterone in neuroprotection and immunomodulation in Parkinson's disease is described in a mouse model in the study by Jarras et al Other neuroactive steroids are involved in complications of sleep deprivation, in the imbalance of inhibitory and excitatory actions during pregnancy that program for poor behavioural outcomes in a sex‐dependent manner later in life, in some psychiatric diseases such as Tourette's syndrome, and in the regulation of mitochondrial function in tauopathies …”