Asanuma Masato, Miyazaki Ikuko
Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Sciences.
Nihon Yakurigaku Zasshi. 2021;156(1):14-20. doi: 10.1254/fpj.20071.
Recently, it has been reported that dysfunction of astrocytes is involved vulnerability of neuronal cells in several neurological disorders. Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine is readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis and release in/from surrounding astrocytes. The expression and release of the zinc-binding protein metallothionein (MT) in astrocytes, which is a strong antioxidant, is induced and exerts neuroprotective in the case of dopaminergic neuronal damage. In addition, the transcription factor Nrf2 induces expression of MT-1 and GSH related molecules. We previously revealed that several antiepileptic drugs, serotonin 5-HT1A receptor agonists, plant-derived chemicals (phytochemicals) increased xCT expression, Nrf2 activation, GSH or MT expression and release in/from astrocytes, and exerted a neuroprotective effect against dopaminergic neurodegeneration in Parkinson's disease model. Our serial studies on neuroprotection via antioxidant defense mechanism of astrocytes have found three target molecular systems of astrocytes for neuroprotection: (1) xCT-GSH synthetic system, (2) Nrf2 system and (3) 5-HT1A receptor-Nrf2-MT system, 5-HT1A-S100β system. In this article, possible neuroprotective strategy for Parkinson's disease has been reviewed targeting antioxidative molecules in astrocytes.
最近，有报道称星形胶质细胞功能障碍与几种神经系统疾病中神经元细胞的易损性有关。谷胱甘肽（GSH）是中枢神经系统中最丰富的内源性抗氧化剂，其底物半胱氨酸很容易氧化成二聚体胱氨酸。由于神经元缺乏胱氨酸转运系统，神经元GSH的合成依赖于通过胱氨酸/谷氨酸交换转运体（xCT）摄取胱氨酸、GSH在周围星形胶质细胞中的合成以及从星形胶质细胞的释放。星形胶质细胞中作为强抗氧化剂的锌结合蛋白金属硫蛋白（MT）的表达和释放，在多巴胺能神经元损伤时被诱导并发挥神经保护作用。此外，转录因子Nrf2可诱导MT-1和GSH相关分子的表达。我们之前发现，几种抗癫痫药物、5-羟色胺5-HT1A受体激动剂、植物源化学物质（植物化学物）可增加xCT表达、Nrf2激活、GSH或MT在星形胶质细胞中的表达和释放，并在帕金森病模型中对多巴胺能神经变性发挥神经保护作用。我们通过星形胶质细胞抗氧化防御机制进行神经保护的系列研究发现了星形胶质细胞用于神经保护的三个靶分子系统：（I）xCT-GSH合成系统、（2）Nrf2系统和（3）5-HT1A受体-Nrf2-MT系统、5-HT1A-S100β系统。本文针对星形胶质细胞中的抗氧化分子，综述了帕金森病可能的神经保护策略。
