De Nicola A F, Gonzalez Deniselle M C, Garay L, Meyer M, Gargiulo-Monachelli G, Guennoun R, Schumacher M, Carreras M C, Poderoso J J
Department of Human Biochemistry, Faculty of Medicine, Instituto de Biologia y Medicina Experimental, University of Buenos Aires, Buenos Aires, Argentina.
J Neuroendocrinol. 2013 Nov;25(11):1095-103. doi: 10.1111/jne.12043.
Progesterone is a neuroprotective, promyelinating and anti-inflammatory factor for the nervous system. Here, we review the effects of progesterone in models of motoneurone degeneration and neuroinflammation. In neurodegeneration of the Wobbler mouse, a subset of spinal cord motoneurones showed increased activity of nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of respiratory chain complexes, and decreased activity and protein expression of Mn-superoxide dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several degrees of motor impairment. Progesterone treatment restored the expression of neuronal markers, decreased the activity of NOS and enhanced complex I respiratory activity and MnSOD2. Long-term treatment with progesterone increased muscle strength, biceps weight and survival. Collectively, these data suggest that progesterone prevented neurodegeneration. To study the effects of progesterone in neuroinflammation, we employed mice with experimental autoimmune encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of the inflammatory mediators tumour necrosis factor (TNF)α and its receptor TNFR1, the microglial marker CD11b, inducible NOS and the toll-like receptor 4. Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells became targets of progesterone anti-inflammatory effects. These results represent a starting point for testing the usefulness of neuroactive steroids in neurological disorders.
孕酮是一种对神经系统具有神经保护、促进髓鞘形成和抗炎作用的因子。在此，我们综述孕酮在运动神经元变性和神经炎症模型中的作用。在摇摆小鼠的神经退行性变中，一部分脊髓运动神经元显示一氧化氮合酶（NOS）活性增加、线粒体内NOS增加、呼吸链复合物活性降低以及2型锰超氧化物歧化酶（MnSOD2）活性和蛋白表达降低。临床上，摇摆小鼠存在不同程度的运动障碍。孕酮治疗可恢复神经元标志物的表达，降低NOS活性，增强复合物I的呼吸活性以及MnSOD2。长期使用孕酮治疗可增加肌肉力量、二头肌重量并延长生存期。总体而言，这些数据表明孕酮可预防神经退行性变。为研究孕酮在神经炎症中的作用，我们使用了实验性自身免疫性脑脊髓炎（EAE）小鼠。EAE小鼠脊髓中炎症介质肿瘤坏死因子（TNF）α及其受体TNFR1、小胶质细胞标志物CD11b、诱导型NOS和Toll样受体4的mRNA水平升高。对EAE小鼠进行孕酮预处理可阻断促炎介质，减少Iba1 +小胶质细胞并减轻EAE的临床症状。因此，反应性胶质细胞成为孕酮抗炎作用的靶点。这些结果是测试神经活性类固醇在神经疾病中效用的起点。
