Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Abstract

Background: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. Methods: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. Results: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. Conclusion: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.

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

“…After treatment, the mice were killed, and the intestines collected. The doses of progesterone administered in the present study were previously shown to be neuroprotective against MPTP in the brains of mice in our previous publications . The rationale for testing the effect of progesterone in the gut is that we previously reported neuroprotection in the brain with progesterone .…”

“…The Laval University Animal Care Committee approved the animal studies. All efforts were made to minimise animal suffering and to reduce the number of mice used . The experiment planned 10 mice per group and, if available, an additional mouse was added to a group.…”

“…Groups containing less than 10 mice were because the gut sample was not of sufficient quality for the measurements reported. These animals were not perfused at death; their brains were fresh frozen to measure DA and metabolites, as well as other dopaminergic markers, and were the subject of previous studies . The guts were kept for the present experiments.…”

“…The guts were kept for the present experiments. A power analysis was not conducted for the present study to estimate the effect size because these mice protocols had already beeen performed and the results for the brain have been reported . This allowed a comparison of the effects in the brain and in the gut.…”

“…Interestingly, the oestrogen compounds (17ß‐oestradiol, raloxifene and G1 ) that we showed to be neuroprotective for brain DA neurones in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD were also found to protect the myenteric DA neurones. Moreover, we have previously shown that progesterone administered both pre and post MPTP treatment protects striatal DA content and transporters against toxicity and that changes in brain‐derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection . Hence, brain dopaminergic neuroprotection with the other ovarian steroid, namely progesterone, could also extend to the periphery.…”