Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab, India.
Pharmacol Rep. 2022 Oct;74(5):790-817. doi: 10.1007/s43440-022-00417-5. Epub 2022 Sep 23.
Insulin resistance and impaired lipoprotein metabolism contribute to a plethora of metabolic and cardiovascular disorders. These alterations have been extensively linked with poor lifestyle choices, such as consumption of a high-fat diet, smoking, stress, and a redundant lifestyle. Moreover, these are also known to increase the co-morbidity of diseases like Type 2 diabetes mellitus and atherosclerosis. Under normal physiological conditions, insulin and lipoproteins exert a neuroprotective role in the central nervous system. However, the tripping of balance between the periphery and center may alter the normal functioning of the brain and lead to neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, depression, and multiple sclerosis. These neurological disorders are further characterized by certain behavioral and molecular changes that show consistent overlap with alteration in insulin and lipoprotein signaling pathways. Therefore, targeting these two mechanisms not only reveals a way to manage the co-morbidities associated with the circle of the metabolic, central nervous system, and cardiovascular disorders but also exclusively work as a disease-modifying therapy for neurological disorders. In this review, we summarize the role of insulin resistance and lipoproteins in the progression of various neurological conditions and discuss the therapeutic options currently in the clinical pipeline targeting these two mechanisms; in addition, challenges faced in designing these therapeutic approaches have also been touched upon briefly.
胰岛素抵抗和脂蛋白代谢受损导致了大量代谢和心血管疾病。这些改变与不良的生活方式选择密切相关,如高脂肪饮食、吸烟、压力和过度的生活方式。此外,这些因素还会增加 2 型糖尿病和动脉粥样硬化等疾病的共病率。在正常生理条件下,胰岛素和脂蛋白在中枢神经系统中发挥神经保护作用。然而,外周和中枢之间的平衡失调可能会改变大脑的正常功能,导致神经退行性疾病,如阿尔茨海默病、帕金森病、中风、抑郁症和多发性硬化症。这些神经退行性疾病的特征还包括某些行为和分子变化,这些变化与胰岛素和脂蛋白信号通路的改变一致。因此,针对这两种机制不仅揭示了一种管理与代谢、中枢神经系统和心血管疾病循环相关的共病的方法,而且还专门作为神经退行性疾病的疾病修饰治疗。在这篇综述中,我们总结了胰岛素抵抗和脂蛋白在各种神经疾病进展中的作用,并讨论了目前针对这两种机制的临床研究中的治疗选择;此外,还简要讨论了设计这些治疗方法所面临的挑战。