Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
Center of Excellence in Regenerative Medicine and Molecular Biology (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570 015, Karnataka, India.
Curr Neuropharmacol. 2022;20(5):893-915. doi: 10.2174/1570159X19666211109141330.
Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved in the cells contributing to on- and off-target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons from Aβ toxicity in Alzheimer's disease (AD) patients. Therefore, the current review delineated the ligands' interaction with 3D-PPARs to modulate neuroprotection, and also deciphered the efficacy of numerous drugs, viz. Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α) and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement that the development of novel PPARs agonists may benefit patients with neurodegeneration, mainly AD patients, which may help mitigate the pathophysiology of dementia, subsequently improving overall the patient's quality of life.
过氧化物酶体增殖物激活受体 (PPARs) 的活性对开发针对神经退行性疾病的新型治疗方法具有重要意义。尽管脑内明显表达了 PPAR-α、PPAR-β/δ 和 PPAR-γ 核受体，但它们在脑生理学和其他神经退行性疾病中的作用仍需要广泛研究。PPAR 信号可以调节参与神经元的各种细胞信号机制，选择性地发挥作用，以促进治疗效果以及 PPAR 配体的不良反应。已经报道了 PPARα、PPARγ 和 PPARβ/δ 的天然和合成配体。PPARα（WY 14.643）和 PPARγ 激动剂可以通过调节氧化还原系统中的线粒体动力学来提供神经保护。这些激动剂的药理作用可以通过保护阿尔茨海默病 (AD) 患者的脆弱神经元免受 Aβ 毒性来提供有效的临床反应。因此，本综述阐述了配体与 3D-PPARs 的相互作用，以调节神经保护，并解析了许多药物的疗效，即 Aβ 聚集抑制剂、疫苗和 γ-分泌酶抑制剂对 AD 的作用；本综述阐明了 PPAR 及其受体同工型在神经系统和人类神经退行性变中的作用。此外，我们还深入讨论了 PPREs 作为脑内有效转录因子的作用，以及 PPAR 激动剂在神经传递、PPAR 伽马共激活因子-1α (PGC-1α) 和线粒体动力学中的作用，在 AD 条件下的神经保护作用。本综述的结论是，新型 PPARs 激动剂的开发可能使神经退行性疾病患者受益，主要是 AD 患者，这可能有助于减轻痴呆症的病理生理学，从而提高患者的整体生活质量。
