RIPK3 抑制剂 GSK872 在 MPTP 诱导的帕金森病小鼠模型中的神经保护和抗炎作用。

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-11-02 DOI:10.1016/j.neuint.2024.105896
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引用次数: 0

摘要

帕金森病(Parkinson's disease,PD)是一种神经退行性疾病,由黑质(substantia nigra,SN)中多巴胺能神经元的丧失引发。最近的研究表明,坏死蛋白沉积参与了多巴胺能神经细胞的死亡和由此引发的神经炎症。在坏死过程中,会形成一个由受体相互作用蛋白激酶 1(RIPK1)、RIPK3 和混合系激酶结构域样蛋白(MLKL)组成的坏死体复合物。虽然RIPK1特异性抑制剂necrostatin-1以及小鼠RIPK3和MLKL基因敲除具有神经保护作用,但RIPK3药理抑制剂在帕金森病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)诱导的帕金森病小鼠模型中的神经保护作用。GSK872 可挽救 MPTP 诱导的运动障碍,并抑制 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,根据生化和组织学分析,GSK872 还抑制了 MPTP 诱导的 p-RIPK3 和 p-MLKL 在多巴胺能神经元和小胶质细胞中的表达增加。GSK872 进一步抑制了 MPTP 小鼠 SN 区域的小胶质细胞活化和炎症介质(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)的表达。通过体外实验,我们验证了 GSK872 对 SH-SY5Y 神经元和 BV2 小胶质细胞坏死的影响。总之,我们的研究结果表明,GSK872 具有神经保护和抗炎作用,因此可能具有治疗帕金森病的潜力。
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Neuroprotective and anti-inflammatory effects of the RIPK3 inhibitor GSK872 in an MPTP-induced mouse model of Parkinson's disease
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.
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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Neuroprotective and anti-inflammatory effects of the RIPK3 inhibitor GSK872 in an MPTP-induced mouse model of Parkinson's disease Editorial Board Altered sex differences related to food intake, hedonic preference, and FosB/deltaFosB expression within central neural circuit involved in homeostatic and hedonic food intake regulation in Shank3B mouse model of autism spectrum disorder Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum Neuron-selective and activity-dependent splicing of BDNF exon I–IX pre-mRNA
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