Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.

孕酮调节神经元和神经胶质细胞中的许多过程，这些过程不直接参与生殖或性行为。如肌萎缩侧索硬化 (ALS) 的 Wobbler 小鼠模型所示，在病理条件下可以更好地观察到几种神经保护作用。Wobbler 小鼠的特征是由于脊髓运动神经元变性导致的前肢萎缩，包括小胶质细胞增生和星形胶质细胞增生。在这里，我们总结了目前关于 Wobbler 神经病理学的孕酮逆转的证据。我们证明黄体酮减少运动神经元空泡化，保留线粒体呼吸复合物 I 活性，降低线粒体表达和一氧化氮合酶活性，增加 Mn 依赖性超氧化物歧化酶，刺激脑源性神经营养因子，增加运动神经元的胆碱能表型，并提高存活率，同时减少与死亡相关的途径。黄体酮还显示出对神经胶质细胞的不同影响，包括增加少突胶质细胞密度和下调星形胶质细胞增生和小胶质细胞增生。这些变化与减少的抗炎标志物有关。在运动行为测试中，增强的神经化学参数伴随着更长的生存期和增加的肌肉力量。因为黄体酮在神经组织中局部代谢为异孕酮 (ALLO)，我们还研究了这种衍生物的神经保护作用。用 ALLO 治疗 Wobbler 小鼠可减少氧化应激和神经胶质病理学，以类似孕酮的方式增加运动神经元的活力和临床结果，表明ALLO可以介导脊髓中的一些孕酮作用。总之，在不同参数中观察到的有益效果支持黄体酮和 ALLO 在运动神经元变性小鼠模型中的多功能特性。这些研究预见了未来使用神经活性类固醇治疗 ALS 等致命疾病的机会。