Liu Jie, Huang Dongping, Xu Jing, Tong Jiabin, Wang Zishan, Huang Li, Yang Yufang, Bai Xiaochen, Wang Pan, Suo Haiyun, Ma Yuanyuan, Yu Mei, Fei Jian, Huang Fang
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Research Center for Translational Medicine and Institute of Heart Failure, East Hospital, Tongji University, Shanghai 200120, China.
Sci Rep. 2015 Oct 26;5:15720. doi: 10.1038/srep15720.
Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson's disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD.
小胶质细胞激活和炎症与神经退行性疾病（如帕金森病，PD）中神经元的进行性凋亡有关。γ-氨基丁酸（GABA）是中枢神经系统中的主要抑制性神经递质，最近已被证明在免疫系统中起抑制作用。噻加宾是一种哌啶衍生物，通过抑制GABA转运体1（GAT 1）增强GABA能传递。在本研究中，我们发现噻加宾预处理可减轻小胶质细胞激活，对黑质纹状体轴提供部分保护，并改善甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中的运动缺陷。在接受MPTP攻击的GAT 1基因敲除小鼠中，噻加宾的保护功能被消除。在另一种由黑质内注射脂多糖（LPS）诱导的PD模型中，证实了噻加宾的小胶质细胞抑制作用及随后的神经保护作用。此外，用GABA能药物预处理可抑制LPS诱导的BV-2小胶质细胞炎症激活以及条件培养基对SH-SY5Y细胞的毒性。核因子κB（NF-κB）核转位的减弱和炎症介质生成的抑制是其潜在机制。我们的结果表明，噻加宾可作为黑质纹状体小胶质细胞激活的制动器，可能是一种治疗PD的新方法。
