Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice.
Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice.
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DOI：
10.1007/s12035-015-9255-6
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发表时间：
2015-10
影响因子：
5.1
通讯作者：
Banik NL
中科院分区：
文献类型：
--
作者：
Samantaray S;Knaryan VH;Shields DC;Cox AA;Haque A;Banik NL
帕金森病（Parkinson's disease，PD）是最常见的神经退行性运动障碍，其主要表现为黑质多巴胺（dopaminergic，DA）能神经元的丢失和脊髓背角神经元的损伤。目前的治疗不能阻止疾病进展。因此，开发有效的治疗策略用于治疗PD是至关重要的。本研究的目的是描述MPTP诱导的帕金森病小鼠（C57 BL/6 N）SN和脊髓中钙蛋白酶介导的炎症和神经变性的参与，从而阐明潜在的治疗靶点。MPTP小鼠黑质酪氨酸羟化酶（TH+）神经元钙蛋白酶表达增加，黑质和脊髓神经元TUNEL阳性神经元显着增加。与对照组相比，MPTP小鼠脊髓中的炎症标志物考克斯-2、caspase-1和NOS-2显著上调。这些参数与星形胶质细胞、小胶质细胞的活化、CD 4 + /CD 8 + T细胞和巨噬细胞的浸润相关。我们发现，CD 4+细胞亚群（Th 1和Tcl 4）的差异扩大MPTP小鼠，这可以通过抑制钙蛋白酶与有效的抑制剂calpeptin调节。用钙蛋白酶肽（25 μg/kg，i. p.）减弱神经胶质活化、T细胞浸润、SN中黑质多巴胺能变性和脊髓中神经元死亡。重要的是，钙蛋白酶肽改善MPTP诱导的步态参数改变（例如，减少步长和增加步频），如通过使用腹平面录像分析时空步态指数所示。这些结果表明，钙蛋白酶在MPTP诱导的黑质和海马神经退行性变过程中起着关键作用，并可能是PD的有效治疗靶点。
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, resulting in dopaminergic (DA) neuronal loss in the substantia nigra pars compacta (SNpc) and damage to extranigral spinal cord neurons. Current therapies do not prevent the disease progression. Hence, developing efficacious therapeutic strategies for treatment of PD is of utmost importance. The goal of this study is to delineate the involvement of calpain-mediated inflammation and neurodegeneration in SN and spinal cord in MPTP-induced parkinsonian mice (C57BL/6N), thereby elucidating potential therapeutic target(s). Increased calpain expression was found localized to tyrosine hydroxylase (TH+) neurons in SN alongside with significantly increased TUNEL positive neurons in SN and spinal cord neurons in MPTP mice. Inflammatory markers Cox-2, caspase-1, and NOS-2 were significantly up-regulated in MPTP mice spinal cord as compared to control. These parameters correlated with the activation of astrocytes, microglia, infiltration of CD4+ / CD8+ T cells and macrophages. We found that subpopulations of CD4+ cells (Th1 & Tregs) were differentially expanded in MPTP mice, which could be regulated by inhibition of calpain with the potent inhibitor calpeptin. Pre-treatment with calpeptin (25 μg/kg, i.p.) attenuated glial activation, T cell infiltration, nigral dopaminergic degeneration in SN, and neuronal death in spinal cord. Importantly, calpeptin ameliorated MPTP-induced altered gait parameters (e.g. reduced stride length and increased stride frequency) as demonstrated by analyses of spatio-temporal gait indices using ventral plane videography. These findings suggest that calpain plays a pivotal role in MPTP-induced nigral and extranigral neurodegenerative processes, and may be a valid therapeutic target in PD.