Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011, USA.
J Neuroinflammation. 2012 Oct 23;9:241. doi: 10.1186/1742-2094-9-241.
Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.
Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin.
Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD.
Collectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients.
帕金森病（PD）是一种破坏性的神经退行性疾病，其特征是进行性运动无力，影响着全球数百万人。最近的证据表明，神经胶质细胞的激活及其炎症反应可能导致 PD 中多巴胺能神经元的进行性退化。目前，尚无有效的神经保护剂可有效减缓疾病进展。在此，我们评估了二丙烯酰蒽醌（apocynin 的氧化代谢物）在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中的抗炎和抗氧化功效。
在 PD 的 MPTP 小鼠模型中分别测试了二丙烯酰蒽醌的预处理和后处理。通过口服灌胃给予二丙烯酰蒽醌处理的 MPTP 小鼠。治疗后进行行为、神经化学和免疫组织化学研究。在黑质纹状体系统中测量神经炎症标志物，如离子钙结合衔接分子 1（Iba-1）、胶质纤维酸性蛋白（GFAP）、gp91phox 和诱导型一氧化氮合酶（iNOS）。还定量了黑质酪氨酸羟化酶（TH）阳性神经元以及氧化标记物 3-硝基酪氨酸（3-NT）、4-羟基壬烯醛（4-HNE）和纹状体多巴胺水平，以评估二丙烯酰蒽醌的神经保护功效。
口服二丙烯酰蒽醌可显著减轻 MPTP 诱导的黑质中小胶质细胞和星形胶质细胞的激活。二丙烯酰蒽醌还完全阻断了 MPTP 诱导的 SN 中 gp91phox 和 iNOS 激活。值得注意的是，二丙烯酰蒽醌还显著抑制了 MPTP 诱导的氧化标记物，包括 SN 中的 3-NT 和 4-HNE 水平。在该 PD 临床前模型中，二丙烯酰蒽醌治疗还显著改善了运动活动，恢复了多巴胺及其代谢物，并保护了多巴胺能神经元及其神经末梢。重要的是，在疾病开始后 3 天给予二丙烯酰蒽醌即可恢复神经化学缺陷。二丙烯酰蒽醌还可阻止 PD 慢性小鼠模型中的疾病进展。
总之，这些结果表明，二丙烯酰蒽醌通过减轻氧化损伤和神经炎症反应，在 PD 的临床前动物模型中表现出显著的神经保护作用。这些发现可能对治疗 PD 患者具有重要的转化意义。
Zotero 插件
