Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation.
Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation.
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噻加宾通过抑制小胶质细胞激活来保护多巴胺能神经元免受神经毒素的侵害
DOI：
10.1038/srep15720
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发表时间：
2015-10-26
影响因子：
4.6
通讯作者：
Huang F
中科院分区：
文献类型：
--
作者：
Liu J;Huang D;Xu J;Tong J;Wang Z;Huang L;Yang Y;Bai X;Wang P;Suo H;Ma Y;Yu M;Fei J;Huang F
小胶质细胞活化和炎症与神经退行性疾病如帕金森病（PD）中的进行性神经元凋亡相关。γ-氨基丁酸（GABA）是中枢神经系统中主要的抑制性神经递质，近年来研究表明其在免疫系统中具有抑制作用。噻加宾是一种哌啶衍生物，通过抑制GABA转运蛋白1（GAT 1）增强GABA能传递.在本研究中，我们发现，噻加宾预处理衰减小胶质细胞活化，提供部分保护黑质纹状体轴和改善运动障碍的甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）小鼠模型的PD。在用MPTP攻击的GAT 1敲除小鼠中，噻加宾的保护功能被消除。在另一种PD模型中，通过黑质内输注脂多糖（LPS）诱导，证实了噻加宾的小胶质细胞抑制和随后的神经保护作用。GABA能药物预处理可抑制LPS诱导的BV-2小胶质细胞的炎性激活和条件培养液对SH-SY 5 Y细胞的毒性。其机制可能与抑制核因子κB（NF-κB）核转位和抑制炎症介质的产生有关。我们的研究结果表明，噻加宾作为刹车黑质纹状体小胶质细胞激活，它可能是一种新的治疗方法PD。
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.