Samim Khan Sabiya, Janrao Sushmita, Srivastava Saurabh, Bala Singh Shashi, Vora Lalitkumar, Kumar Khatri Dharmendra
Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
Biochem Pharmacol. 2023 Apr;210:115496. doi: 10.1016/j.bcp.2023.115496. Epub 2023 Mar 11.
Neuroinflammation is a critical degradative condition affecting neurons in the brain. Progressive neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease (PD) have been strongly linked to neuroinflammation. The trigger point for inflammatory conditions in the cells and body is the physiological immune system. The immune response mediated by glial cells and astrocytes can rectify the physiological alterations occurring in the cell for the time being but prolonged activation leads to pathological progression. The proteins mediating such an inflammatory response, as per the available literature, are undoubtedly GSK-3β, NLRP3, TNF, PPARγ, and NF-κB, along with a few other mediatory proteins. NLRP3 inflammasome is undeniably a principal instigator of the neuroinflammatory response, but the regulatory pathways controlling its activation are still unclear, besides less clarity for the interplay between different inflammatory proteins. Recent reports have suggested the involvement of GSK-3β in regulating NLRP3 activation, but the exact mechanistic pathway remains vague. In the current review, we attempt to provide an elaborate description of crosstalk between inflammatory markers and GSK-3β mediated neuroinflammation progression, linking it to regulatory transcription factors and posttranslational modification of proteins. The recent clinical therapeutic advances targeting these proteins are also discussed in parallel to provide a comprehensive view of the progress made in PD management and lacunas still existing in the field.
神经炎症是一种影响大脑神经元的关键降解性病症。诸如阿尔茨海默病和帕金森病（PD）等进行性神经退行性疾病与神经炎症密切相关。细胞和身体中炎症状态的触发点是生理免疫系统。由神经胶质细胞和星形胶质细胞介导的免疫反应可以暂时纠正细胞中发生的生理改变，但长期激活会导致病理进展。根据现有文献，介导这种炎症反应的蛋白质无疑是糖原合成酶激酶-3β（GSK-3β）、NOD样受体蛋白3（NLRP3）、肿瘤坏死因子（TNF）、过氧化物酶体增殖物激活受体γ（PPARγ）和核因子κB（NF-κB），以及其他一些介导蛋白。NLRP3炎性小体无疑是神经炎症反应的主要煽动者，但其激活的调控途径仍不清楚，不同炎症蛋白之间的相互作用也不太明确。最近的报告表明GSK-3β参与调节NLRP3的激活，但其确切的机制途径仍不明确。在本综述中，我们试图详细描述炎症标志物与GSK-3β介导的神经炎症进展之间的相互作用，并将其与调节性转录因子和蛋白质的翻译后修饰联系起来。同时还讨论了针对这些蛋白质的最新临床治疗进展，以全面了解PD治疗取得的进展以及该领域仍然存在的不足。
