Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
Neurotoxicology. 2010 Jan;31(1):55-66. doi: 10.1016/j.neuro.2009.12.001. Epub 2009 Dec 5.
Anti-inflammatory strategies receive growing attention for their potential to prevent pathological deterioration in disorders such as Parkinson's disease, which is accompanied by inflammatory reactions that might play a critical role in the degeneration of nigral dopaminergic neurons. We investigated the influence of dexamethasone - a potent synthetic member of the glucocorticoids class of steroid hormones that acts as an anti-inflammatory - on the degeneration of the dopaminergic neurons of rats observed after intranigral injection of thrombin, a serine protease that induces inflammation through microglia proliferation and activation. We evaluated tyrosine hydroxylase (TH)-positive neurons as well as astroglial and microglial populations; dexamethasone prevented the loss of astrocytes but was unable to stop microglial proliferation induced by thrombin. Moreover, dexamethasone produced alterations in the levels of nexin and the thrombin receptor PAR-1, and facilitated accumulation of alpha-synuclein induced by thrombin in dopaminergic neurons. Dexamethasone increased oxidative stress and expression of monoamine oxidase A and B, along with changes on different MAP kinases related to degenerative processes, resulting in a bigger loss of dopaminergic neurons after intranigral injection of thrombin in dexamethasone-treated animals. It is interesting to ascertain that inhibition of monoamine oxidase by tranylcypromine prevented neurodegeneration of dopaminergic neurons, thus suggesting that the deleterious effects of dexamethasone might be mediated by monoamine oxidase.
抗炎策略因其在帕金森病等疾病中的潜在应用而受到越来越多的关注，这些疾病伴随着炎症反应，这些炎症反应可能在黑质多巴胺能神经元变性中发挥关键作用。我们研究了地塞米松（一种糖皮质激素类甾体激素的强效合成成员，具有抗炎作用）对凝血栓蛋白酶诱导的大鼠黑质多巴胺能神经元变性的影响，凝血栓蛋白酶是一种丝氨酸蛋白酶，通过小胶质细胞增殖和激活引起炎症。我们评估了酪氨酸羟化酶（TH）阳性神经元以及星形胶质细胞和小胶质细胞群体；地塞米松可预防星形胶质细胞丢失，但不能阻止凝血栓蛋白酶诱导的小胶质细胞增殖。此外，地塞米松改变了连接蛋白和凝血酶受体 PAR-1 的水平，并促进了凝血酶诱导的α-突触核蛋白在多巴胺能神经元中的积累。地塞米松增加了氧化应激和单胺氧化酶 A 和 B 的表达，以及与退行性过程相关的不同 MAP 激酶的变化，导致在给予地塞米松的动物中，凝血栓蛋白酶脑内注射后多巴胺能神经元的损失更大。有趣的是，通过曲安西龙抑制单胺氧化酶可防止多巴胺能神经元的神经变性，因此提示地塞米松的有害作用可能是由单胺氧化酶介导的。
