MP-10 (PF-2545920) is a selective inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly enriched in the striatum, nucleus accumbens, olfactory tubercle, and substantia nigra. The therapeutic effect of MP-10 has been reported in psychiatric and neurodegenerative disorders such as schizophrenia, depression, and Huntington’s disease. However, the effect of MP-10 in Parkinson’s disease (PD) has not been reported to date. In this study, we examined the effect of MP-10 in neuroinflammation and PD mouse models. MP-10 inhibited nitric oxide, tumor necrosis factor alpha, and interleukin (IL)-6 production, while it promoted IL-10 production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Subsequent western blot and reverse transcription polymerase chain reaction analyses showed that MP-10 reduced the mRNA and protein levels of inducible nitric oxide synthase, cyclooxygenase-2, proinflammatory cytokines, and matrix metalloproteinase-3, −8, and − 9 in LPS-stimulated BV2 cells. Further mechanistic studies revealed that MP-10 exerts anti-inflammatory effects by inhibiting the phosphorylation of c-Jun N-terminal kinase and Akt, reducing the activity of nuclear factor-kappa B/activator protein-1, and upregulating the nuclear factor erythroid 2-related factor 2/antioxidant response element and protein kinase A/cAMP response element-binding protein signaling pathways. The anti-inflammatory effect of MP-10 was confirmed in vivo. Specifically, MP-10 inhibited microglial activation and proinflammatory gene expression in the brains of LPS-injected mice. Moreover, MP-10 rescued behavioral deficits and recovered dopaminergic neuronal cell death in the brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice. MP-10 also reduced microglial activation in this PD mouse model. These data collectively suggest that MP-10 may have therapeutic potential in PD and other neuroinflammatory disorders.

Graphical Abstract

MP-10 (PF-2545920) 是磷酸二酯酶 10A (PDE10A) 的选择性抑制剂，该酶在纹状体、伏隔核、嗅结节和黑质中高度富集。MP-10 在精神分裂症、抑郁症和亨廷顿病等精神和神经退行性疾病中的治疗效果已有报道。然而，迄今为止尚未报道 MP-10 在帕金森病 (PD) 中的作用。在这项研究中，我们检查了 MP-10 在神经炎症和 PD 小鼠模型中的作用。MP-10 抑制一氧化氮、肿瘤坏死因子 α 和白细胞介素 (IL)-6 的产生，同时它促进脂多糖 (LPS) 刺激的 BV2 小胶质细胞中 IL-10 的产生。随后的蛋白质印迹和逆转录聚合酶链反应分析表明，MP-10 降低了 LPS 刺激的诱导型一氧化氮合酶、环氧合酶-2、促炎细胞因子和基质金属蛋白酶-3、-8 和-9 的 mRNA 和蛋白质水平。 BV2 细胞。进一步的机制研究表明，MP-10 通过抑制 c-Jun N 端激酶和 Akt 的磷酸化，降低核因子-κB/激活蛋白-1 的活性，并上调核因子红细胞 2 来发挥抗炎作用-相关因子 2/抗氧化反应元件和蛋白激酶 A/cAMP 反应元件结合蛋白信号通路。MP-10 的抗炎作用在体内得到证实。具体来说，MP-10 抑制注射 LPS 的小鼠大脑中的小胶质细胞活化和促炎基因表达。此外，MP-10 在 1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的 PD 小鼠的大脑中挽救了行为缺陷并恢复了多巴胺能神经元细胞死亡。MP-10 还减少了该 PD 小鼠模型中的小胶质细胞活化。这些数据共同表明 MP-10 可能对 PD 和其他神经炎症性疾病具有治疗潜力。

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