Reduction in Nesfatin-1 Levels in the Cerebrospinal Fluid and Increased Nigrostriatal Degeneration Following Ventricular Administration of Anti-nesfatin-1 Antibody in Mice.
Reduction in Nesfatin-1 Levels in the Cerebrospinal Fluid and Increased Nigrostriatal Degeneration Following Ventricular Administration of Anti-nesfatin-1 Antibody in Mice.
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DOI：
10.3389/fnins.2021.621173
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发表时间：
2021
影响因子：
4.3
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Chen H;Li X;Ma H;Zheng W;Shen X
Nesfatin-1是与中枢多巴胺能系统关系密切的几种脑肠肽之一。我们前期的研究表明nesfatin-1能够保护黑质多巴胺能神经元免受1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的神经毒性。最近的一项研究还显示，帕金森病（PD）患者的nesfatin-1血液水平降低。本研究旨在探讨脑脊液（CSF）中nesfatin-1减少是否会导致黑质纹状体系统变性。使用脑室内（ICV）注射技术将抗nesfatin-1抗体直接施用到脑的侧脑室中。酶联免疫吸附试验（ELISA）结果显示，每天一次向侧脑室注射抗nesfatin-1抗体，持续2周，导致CSF中nesfatin-1水平显著降低（93.1%）。用抗nesfatin-1抗体处理导致黑质丘脑部（SNpc）中TH阳性（TH+）多巴胺能神经元的大量损失（23%），如免疫荧光染色所示，通过高效液相色谱（HPLC）检测到纹状体中多巴胺及其代谢物的耗尽，透射电镜下可见黑质致密部多巴胺能神经元核固缩、线粒体损伤。此外，来自我们的Western印迹和ELISA实验的结果表明，抗nesfatin-1抗体注射诱导了半胱天冬酶-3活化的上调，增加了p-ERK的表达，并升高了SNpc中的脑源性神经营养因子（BDNF）水平。总之，这些观察结果表明，减少nesfatin-1在大脑中可能会导致黑质纹状体多巴胺能系统变性，这种影响可能是通过介导的线粒体功能障碍相关的细胞凋亡。我们的数据支持nesfatin-1在维持黑质纹状体多巴胺能系统的正常生理功能的作用。
Nesfatin-1 is one of several brain-gut peptides that have a close relationship with the central dopaminergic system. Our previous studies have shown that nesfatin-1 is capable of protecting nigral dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. A recent study also revealed a reduced blood level of nesfatin-1 in patients with Parkinson’s disease (PD). The current study was designed to investigate whether reduced nesfatin-1 in cerebrospinal fluid (CSF) induces nigrostriatal system degeneration. An intra-cerebroventricular (ICV) injection technique was used to administer anti-nesfatin-1 antibody directly into the lateral ventricle of the brain. Enzyme-linked immunosorbent assay (ELISA) results showed that ICV injection of anti-nesfatin-1 antibody into the lateral ventricle of the brain once daily for 2 weeks caused a significant reduction in nesfatin-1 levels in the CSF (93.1%). Treatment with anti-nesfatin-1 antibody resulted in a substantial loss (23%) of TH-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc), as shown by immunofluorescence staining, a depletion in dopamine and its metabolites in the striatum detected by high-performance liquid chromatography (HPLC), and obvious nuclear shrinkage and mitochondrial lesions in dopaminergic neurons in the SNpc detected by transmission electron microscopy (TEM). Furthermore, the results from our Western blot and ELISA experiments demonstrated that anti-nesfatin-1 antibody injection induced an upregulation of caspase-3 activation, increased the expression of p-ERK, and elevated brain-derived neurotrophic factor (BDNF) levels in the SNpc. Taken together, these observations suggest that reduced nesfatin-1 in the brain may induce nigrostriatal dopaminergic system degeneration; this effect may be mediated via mitochondrial dysfunction-related apoptosis. Our data support a role of nesfatin-1 in maintaining the normal physiological function of the nigrostriatal dopaminergic system.