在帕金森病临床前动物模型中,线粒体泊金霉素治疗可防止神经炎症和多巴胺能神经退行性变。

IF 5.2 3区 医学 Q1 NEUROSCIENCES Journal of Neuroimmune Pharmacology Pub Date : 2016-06-01 Epub Date: 2016-02-02 DOI:10.1007/s11481-016-9650-4
Anamitra Ghosh, Monica R Langley, Dilshan S Harischandra, Matthew L Neal, Huajun Jin, Vellareddy Anantharam, Joy Joseph, Timothy Brenza, Balaji Narasimhan, Arthi Kanthasamy, Balaraman Kalyanaraman, Anumantha G Kanthasamy
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引用次数: 0

摘要

线粒体功能障碍、氧化应激和神经炎症已被认为是导致帕金森病(PD)多巴胺能神经元逐渐退化的关键介质。目前,我们还缺乏一种能够干预所有关键病理机制的药理制剂,这种药理制剂比针对单一退化机制的化合物具有更好的神经保护功效。在此,我们研究了一种新合成的口服阿朴昔宁衍生物--阿朴昔宁(Mito-Apo),它以线粒体为靶点,是否能在帕金森病的细胞和动物模型中防止氧化损伤、神经胶质介导的炎症和黑质神经退行性变。在原代间脑培养物中处理 Mito-Apo 能显著减轻 1-甲基-4-苯基吡啶鎓(MPP(+))诱导的酪氨酸羟化酶(TH)阳性神经细胞和神经元的丢失。Mito-Apo还能减少MPP(+)诱导的神经胶质细胞活化和诱导型一氧化氮合酶(iNOS)表达的增加。此外,Mito-Apo 还能降低原代间脑培养物中硝基酪氨酸(3-NT)和 4-羟基壬烯醇(4-HNE)的水平。重要的是,我们评估了 Mito-Apo 在 MPTP 中枢神经缺损症小鼠模型中的神经保护特性,它能恢复 MPTP 治疗小鼠的行为表现。黑质多巴胺能神经元的免疫组织学分析和单胺测定进一步证实了 Mito-Apo 对 MPTP 诱导的黑质多巴胺能神经元丧失的神经保护作用。Mito-Apo具有良好的脑生物利用度,还能显著减轻MPTP诱导的黑质(SN)氧化标记。此外,口服 Mito-Apo 能显著抑制 MPTP 诱导的神经胶质细胞活化、促炎细胞因子上调、iNOS 和 IBA1 阳性细胞中的 gp91phox。总之,这些结果表明,新型线粒体靶向化合物 Mito-Apo 通过减轻氧化损伤和神经炎症过程,在细胞和临床前帕金森病动物模型中表现出深远的神经保护作用。
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Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease.

Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson's disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP(+)-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.

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来源期刊
CiteScore
13.60
自引率
0.00%
发文量
18
审稿时长
6-12 weeks
期刊介绍: The aims of the Journal of Neuroimmune Pharmacology are to promote the dissemination, interest, and exchange of new and important discoveries for the pharmacology and immunology of the nervous system. The aims parallel that of the Society on NeuroImmune Pharmacology by increasing the fundamental understanding of neurologic and neuropsychiatric disorders affected by the immune system or vice versa and towards pharmacologic measures that lead, either to a better understanding of disease mechanisms, or by improving disease outcomes. The scope of JNIP includes all primary works and reviews into the etiology, prevention, and treatment of neuroimmune and nervous system diseases affected by disordered immunity. Original studies serving to define neuroimmune modulation of environmental or endogenous cues such as toxins and drugs of abuse, hormones, and cytokines are welcome. JNIP will serve as a reliable source of interdisciplinary information bridging the fields of pharmacology, immunology, and neuroscience.
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