Exposure to elevated levels of manganese (Mn) causes manganism, a neurological disorder with similar characteristics to those of Parkinson’s disease (PD). Valproic acid (VPA), an antiepileptic, is known to inhibit histone deacetylases and exert neuroprotective effects in many experimental models of neurological disorders. In the present study, we investigated if VPA attenuated Mn-induced dopaminergic neurotoxicity and the possible mechanisms involved in VPA’s neuroprotection, focusing on modulation of astrocytic glutamate transporters (glutamate aspartate transporter, GLAST and glutamate transporter 1, GLT-1) and histone acetylation in H4 astrocyte culture and mouse models. The results showed that VPA increased promoter activity, mRNA/protein levels of GLAST/GLT-1 and glutamate uptake, and reversed Mn-reduced GLAST/GLT-1 in in vitro astrocyte cultures. VPA also attenuated Mn-induced reduction of GLAST and GLT-1 mRNA/protein levels in midbrain and striatal regions of the mouse brain when VPA (200 mg/kg, i.p., daily, 21 d) was administered 30 min prior to Mn exposure (30 mg/kg, intranasal instillation, daily, 21 d). Importantly, VPA attenuated Mn-induced dopaminergic neuronal damage by reversing Mn-induced decrease of tyrosine hydroxylase (TH) mRNA/protein levels in the nigrostriatal regions. VPA also reversed Mn-induced reduction of histone acetylation in astrocytes as well as mouse brain tissue. Taken together, VPA exerts attenuation against Mn-induced decrease of astrocytic glutamate transporters parallel with reversing Mn-induced dopaminergic neurotoxicity and Mn-reduced histone acetylation. Our findings suggest that VPA could serve as a potential neuroprotectant against Mn neurotoxicity as well as other neurodegenerative diseases associated with excitotoxicity and impaired astrocytic glutamate transporters.

暴露于高水平的锰 (Mn) 会导致锰中毒，这是一种与帕金森病 (PD) 具有相似特征的神经系统疾病。丙戊酸 (VPA) 是一种抗癫痫药，已知可抑制组蛋白脱乙酰酶，并在许多神经系统疾病的实验模型中发挥神经保护作用。在本研究中，我们研究了 VPA 是否减轻 Mn 诱导的多巴胺能神经毒性以及 VPA 神经保护中涉及的可能机制，重点是星形胶质细胞谷氨酸转运蛋白（谷氨酸天冬氨酸转运蛋白，GLAST 和谷氨酸转运蛋白 1，GLT-1）的调节和组蛋白乙酰化H4 星形胶质细胞培养和小鼠模型。结果表明，VPA 增加了启动子活性、GLAST/GLT-1 的 mRNA/蛋白质水平和谷氨酸摄取，并在体外星形胶质细胞培养物中逆转锰还原的 GLAST/GLT-1。当在 Mn 暴露前 30 分钟给予 VPA（200 mg/kg，ip，每天，21 天）时，VPA 还减弱了 Mn 诱导的小鼠大脑中脑和纹状体区域 GLAST 和 GLT-1 mRNA/蛋白水平的降低（ 30 mg/kg，鼻内滴注，每天，21 d)。重要的是，VPA 通过逆转 Mn 诱导的黑质纹状体区域酪氨酸羟化酶 (TH) mRNA/蛋白水平的降低来减轻 Mn 诱导的多巴胺能神经元损伤。VPA 还逆转了 Mn 诱导的星形胶质细胞和小鼠脑组织中组蛋白乙酰化的减少。总之，VPA 对 Mn 诱导的星形胶质细胞谷氨酸转运蛋白减少具有减弱作用，同时逆转 Mn 诱导的多巴胺能神经毒性和 Mn 减少的组蛋白乙酰化。