Parkinson's disease (PD) is characterized by the selective loss of nigrostriatal dopamine neurons associated with microglial activation. Inhibition of the inflammatory response elicited by activated microglia could be an effective strategy to alleviate the progression of PD. Here, we synthesized 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-N-(2-hydroxyethyl)-2-oxoacetamide (CDMPO) and studied its protective anti-inflammatory mechanisms following lipopolysaccharide (LPS)-induced neuroinflammation in vitro and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo. CDMPO and its parent compound, rimonabant, significantly attenuated nitric oxide (NO) production in LPS-stimulated primary microglia and BV2 cells. Furthermore, CDMPO significantly inhibited the release of proinflammatory cytokines and prostaglandin E2 (PGE2) by activated BV2 cells, also suppressed expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Mechanistically, CDMPO attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB), inhibitor of kappa B alpha (IκBα), and p38 phosphorylation in BV2 cells. MPTP intoxication of mice results in glial activation, tyrosine hydroxylase (TH) depletion, and significant behavioral deficits. Prophylactic treatment with CDMPO decreased proinflammatory molecules via NF-κB and p38 mitogen-activated protein kinase signaling, resulting in protection of dopaminergic neurons and improved behavioral impairments. These results suggest that CDMPO is a promising neuroprotective agent for the prevention and treatment of microglia-mediated neuroinflammatory conditions and may be useful for behavioral improvement in PD phenotype.

中文翻译：

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2-（5-（4-氯苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-基）-N-（2-羟乙基）-2-氧乙酰胺（CDMPO）具有抗-小胶质细胞的炎症特性，可预防帕金森氏病MPTP小鼠模型的神经元和行为缺陷。

帕金森氏病（PD）的特征是与小胶质细胞活化相关的黑质纹状体多巴胺神经元选择性丢失。抑制活化的小胶质细胞引起的炎症反应可能是减轻PD进展的有效策略。在这里，我们合成了2-（5-（4-氯苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-基）-N-（2-羟乙基）-2-氧乙酰胺（ CDMPO）并研究了其在体外脂多糖（LPS）诱导的神经炎症和体内1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的神经毒性后的保护性抗炎机制。CDMPO及其母体化合物利莫那班可显着降低LPS刺激的原代小胶质细胞和BV2细胞中一氧化氮（NO）的产生。此外，CDMPO通过活化的BV2细胞显着抑制促炎细胞因子和前列腺素E2（PGE2）的释放，还抑制诱导型一氧化氮合酶（iNOS）和环氧合酶2（COX-2）的表达。从机理上讲，CDMPO减弱了LPS诱导的核因子-κB（NF-κB），κBα抑制剂（IκBα）和pV2细胞中p38磷酸化的激活。小鼠的MPTP中毒会导致神经胶质激活，酪氨酸羟化酶（TH）耗竭和明显的行为缺陷。CDMPO的预防性治疗通过NF-κB和p38丝裂原活化的蛋白激酶信号传导减少了促炎分子，从而保护了多巴胺能神经元并改善了行为障碍。