Litim Nadhir, Morissette Marc, Di Paolo Thérèse
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada.
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada.
Neuropharmacology. 2017 May 1;117:209-218. doi: 10.1016/j.neuropharm.2017.02.007. Epub 2017 Feb 10.
Progesterone neuroprotection of striatal dopamine (DA) in male mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was previously reported when administered before MPTP or an hour after. A dose of MPTP to induce a partial lesion was used to model early stages or prodromal Parkinson. We hypothesized that brain DA can be restored by progesterone administered early (24 h) or later (5 days) after MPTP. Male mice received 4 injections of MPTP (8 mg/kg) and progesterone (8 mg/kg) once daily for 5 days started 24 h or 5 days after MPTP. The lesion decreased striatal DA and its metabolites but not serotonin contents. MPTP mice treated with progesterone starting 24 h but not 5 days after MPTP had higher striatal DA and its metabolites content than vehicle-treated MPTP mice. Striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding decreased in lesioned mice and were corrected with progesterone treatment starting 24 h but not 5 days after MPTP. Striatal glial fibrillary acidic protein (GFAP) levels, a marker of activated astrocytes, were elevated by the MPTP lesion and were corrected with progesterone treatment starting 24 h after MPTP. Striatal brain derived neurotrophic factor (BDNF) levels were decreased by the MPTP lesion and were prevented by progesterone treatments whereas no change of Akt, GSK3β, ERK1 and 2 and their phosphorylated forms were observed. Thus, progesterone administered after MPTP in mice protected dopaminergic neurons through modulation of neuroinflammation and BDNF. In humans, progesterone could possibly be used as a disease-modifying drug in prodromal Parkinson.
先前有报道称，在雄性小鼠用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤前或损伤后一小时给予孕酮，可对纹状体多巴胺（DA）起到神经保护作用。使用一定剂量的MPTP诱导部分损伤，以此模拟帕金森病的早期阶段或前驱期。我们假设，在MPTP损伤后早期（24小时）或晚期（5天）给予孕酮可以恢复脑内多巴胺水平。雄性小鼠在接受4次MPTP注射（8mg/kg）后，于MPTP注射后24小时或5天开始，每天注射一次孕酮（8mg/kg），持续5天。损伤降低了纹状体多巴胺及其代谢产物的水平，但不影响血清素含量。在MPTP注射后24小时而非5天开始用孕酮治疗的MPTP小鼠，其纹状体多巴胺及其代谢产物含量高于用赋形剂处理的MPTP小鼠。纹状体多巴胺转运体（DAT）和囊泡单胺转运体2（VMAT2）的特异性结合在损伤小鼠中降低，并且在MPTP注射后24小时而非5天开始用孕酮治疗可使其得到纠正。纹状体胶质纤维酸性蛋白（GFAP）水平作为活化星形胶质细胞的标志物，在MPTP损伤后升高，并在MPTP注射后24小时开始用孕酮治疗可使其得到纠正。MPTP损伤降低了纹状体脑源性神经营养因子（BDNF）水平，而孕酮治疗可预防这种降低，同时未观察到Akt、GSK3β、ERK1和2及其磷酸化形式的变化。因此，在小鼠MPTP损伤后给予孕酮可通过调节神经炎症和BDNF来保护多巴胺能神经元。在人类中，孕酮可能作为前驱期帕金森病的疾病修饰药物。
