Park Jin-Sun, Leem Yea-Hyun, Kim Do-Yeon, Park Jae-Min, Kim Seong-Eun, Kim Hee-Sun
Department of Molecular Medicine, Inflammation-Cancer Microenvironment Research Center, School of Medicine, Ewha Womans University, Seoul, South Korea.
Department of Molecular Medicine, Inflammation-Cancer Microenvironment Research Center, School of Medicine, Ewha Womans University, Seoul, South Korea; Department of Brain & Cognitive Sciences, Ewha Womans University, Seoul, South Korea.
Neurochem Int. 2024 Dec;181:105896. doi: 10.1016/j.neuint.2024.105896. Epub 2024 Nov 2.
Parkinson's disease (PD) is a neurodegenerative disorder triggered by the loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have demonstrated that necroptosis is involved in dopaminergic neuronal cell death and the resulting neuroinflammation. During the process of necroptosis, a necrosome complex is formed consisting of the proteins receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). Although the neuroprotective effects of the RIPK1-specific inhibitor necrostatin-1, as well as RIPK3 and MLKL knockout in mice, have been described, the effects of RIPK3 pharmacological inhibitors have not yet been reported in animal models of PD. In the present study, we investigated the neuroprotective effects of GSK872, a specific RIPK3 inhibitor, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. GSK872 rescued MPTP-induced motor impairment and inhibited tyrosine hydroxylase-positive dopaminergic cell death in the SN and striatum. Additionally, GSK872 inhibited the MPTP-induced increase in the expression of p-RIPK3 and p-MLKL in both the dopaminergic neurons and microglia, as assessed by biochemical and histological analyses. GSK872 further inhibited microglial activation and the expression of inflammatory mediators including NLRP3, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha, and inducible nitric oxide synthase in the SN region of MPTP mice. Using in vitro experiments, we validated the effects of GSK872 on necroptosis in SH-SY5Y neuronal and BV2 microglial cells. Overall, our results suggest that GSK872 exerts neuroprotective and anti-inflammatory effects, and may thus have therapeutic potential for PD.
帕金森病（PD）是一种由黑质（SN）中多巴胺能神经元丧失引发的神经退行性疾病。最近的研究表明，坏死性凋亡参与了多巴胺能神经元细胞死亡及由此产生的神经炎症。在坏死性凋亡过程中，由受体相互作用蛋白激酶1（RIPK1）、RIPK3和混合谱系激酶结构域样蛋白（MLKL）组成的坏死小体复合物形成。尽管已描述了RIPK1特异性抑制剂坏死素-1以及小鼠中RIPK3和MLKL基因敲除的神经保护作用，但RIPK3药理抑制剂在PD动物模型中的作用尚未见报道。在本研究中，我们研究了特异性RIPK3抑制剂GSK872在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中的神经保护作用。GSK872挽救了MPTP诱导的运动障碍，并抑制了SN和纹状体中酪氨酸羟化酶阳性多巴胺能细胞的死亡。此外，通过生化和组织学分析评估，GSK872抑制了MPTP诱导的多巴胺能神经元和小胶质细胞中p-RIPK3和p-MLKL表达的增加。GSK872进一步抑制了MPTP小鼠SN区域中小胶质细胞的活化以及包括NLRP3、白细胞介素（IL）-1β、IL-6、肿瘤坏死因子-α和诱导型一氧化氮合酶在内的炎症介质的表达。通过体外实验，我们验证了GSK872对SH-SY5Y神经元和BV2小胶质细胞坏死性凋亡的影响。总体而言，我们的结果表明GSK872具有神经保护和抗炎作用，因此可能对PD具有治疗潜力。
