Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and loss of both motor and non-motor features. Several clinical and preclinical studies have provided evidence that estrogen therapy reduces the risk of PD but have limitations in terms of adverse peripheral effects. Therefore, we examined the potential beneficial effects of the brain-selective estrogen prodrug, 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED) on nigrostriatal dopaminergic neurodegeneration and behavioral abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wild-type mice were treated with daily subcutaneous injections of DHED (50 and 100 µg/kg) or vehicle for four weeks. To produce PD-like symptoms, mice were injected with MPTP (18 mg/kg in saline; intraperitoneally) four times at 2-hr intervals for one day. After behavioral examination, mice were sacrificed, and the brains were isolated for neurochemical and morphological examinations. MPTP injected mice exhibited loss of dopaminergic neurons and fibers in substantia nigra and striatum respectively, along with impaired motor function at day 7 post MPTP injection. These phenotypes were associated with significantly increased oxidative stress and inflammatory responses in the striatum regions. DHED treatments significantly mitigated behavioral impairments and dopaminergic neurodegeneration induced by MPTP. We further observed that DHED treatment suppressed oxidative stress and inflammation in the striatum of MPTP treated mice when compared to vehicle treated mice. In conclusions, our findings suggest that DHED protects dopaminergic neurons from MPTP toxicity in mouse model of PD and support a beneficial effect of brain-selective estrogen in attenuating neurodegeneration and motor symptoms in PD-related neurological disorders.

帕金森病 (PD) 的特征是黑质中多巴胺能神经元的进行性退化以及运动和非运动特征的丧失。几项临床和临床前研究提供的证据表明雌激素治疗可降低 PD 的风险，但在不良外周效应方面存在局限性。因此，我们检查了脑选择性雌激素前药 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED) 对黑质纹状体多巴胺能神经变性和 1-甲基-4-苯基行为异常的潜在有益作用。 1,2,3,6-四氢吡啶 (MPTP) PD 小鼠模型。野生型小鼠每天皮下注射 DHED（50 和 100 µg/kg）或载体治疗 4 周。为了产生 PD 样症状，给小鼠注射 MPTP（生理盐水中 18 mg/kg；腹腔注射）4 次，间隔 2 小时，持续 1 天。行为检查后，处死小鼠，分离大脑进行神经化学和形态学检查。注射 MPTP 的小鼠在注射 MPTP 后第 7 天分别表现出黑质和纹状体中多巴胺能神经元和纤维的丧失，以及运动功能受损。这些表型与纹状体区域的氧化应激和炎症反应显着增加有关。DHED 治疗显着减轻了由 MPTP 引起的行为障碍和多巴胺能神经变性。我们进一步观察到，与载体处理的小鼠相比，DHED 处理抑制了 MPTP 处理的小鼠纹状体中的氧化应激和炎症。在结论中，