Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease
Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease
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DOI：
10.1074/jbc.m116.714824
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发表时间：
2016-07-15
影响因子：
4.8
通讯作者：
Pahan, Kalipada
中科院分区：
文献类型：
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作者：
Chandra, Goutam;Rangasamy, Suresh B.;Pahan, Kalipada
帕金森病(PD)是仅次于阿尔茨海默病的人类最常见的神经退行性疾病，尽管有大量的研究，但目前尚无阻断性治疗方法。最近的研究表明，帕金森病的发病机制包括先天免疫过程和获得性免疫过程。相应地，我们发现在1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)中毒小鼠的黑质致密部和血清中，RANTES(调节正常T细胞表达和分泌的激活)和Eoaxin(参与T细胞运输的趋化因子)在体内迅速增加。与年龄匹配的对照组相比，死后帕金森病患者大脑黑质致密部中RANTES和Eoaxin的表达也上调。因此，我们研究了中和RANTES和嗜酸性粒细胞趋化因子对MPTP中毒小鼠黑质纹状体变性的保护作用。有趣的是，在外周给药后，针对RANTES和嗜酸性粒细胞趋化因子的功能性阻断抗体减少了CD4+和CDS+T细胞向黑质的渗透，减弱了黑质促炎分子的表达，并抑制了黑质胶质细胞的激活。这些发现与MPTP中毒小鼠的多巴胺能神经元保护、纹状体神经递质正常化和运动功能改善平行。因此，我们得出结论，减弱趋化因子依赖的获得性免疫反应可能对P1)患者有治疗益处。
Parkinson disease (PD) is second only to Alzheimer disease as the most common human neurodegenerative disorder, Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found a rapid increase in RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also up-regulated in the substantia nigra pars compacta of post-mortem PD brains as compared with age -matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP -intoxicated mice, Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4+ and CDS+ T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP -intoxicated mice. Therefore, we conclude that attenuation of the chemokine-dependent adaptive immune response may be of therapeutic benefit for P1) patients.