Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab,India.
Centre for Excellence in Functional Foods, Food & Nutritional Biotechnology Division, National Agri-Food Biotechnology Institute, Knowledge City, Sector 81, SAS Nagar, Punjab, 140306,India.
Curr Neurovasc Res. 2021;18(5):497-507. doi: 10.2174/1567202619666211217140954.
PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson's disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD.
In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD.
PD was induced using a bilateral intranigral administration of MPTP in Sprague Dawley rats, and different parameters were evaluated.
Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents.
Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.
过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）是已知的线粒体生物发生的主调控因子。它也是过氧化物酶体增殖物激活受体 -γ（PPARγ）的共激活因子，在几种神经退行性疾病中发挥作用，包括帕金森病（PD）。这些蛋白质水平的耗竭与氧化应激、炎症和 DNA 损伤有关，所有这些都已知会导致 PD 的发病机制。
在本研究中，使用 PPARγ 激动剂（GW1929）和 PGC-1α 激活剂（α-硫辛酸）联合治疗来改善与 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 模型相关的认知缺陷、氧化应激和炎症。
通过双侧纹状体注射 MPTP 在 Sprague Dawley 大鼠中诱导 PD，并评估不同参数。
我们的研究表明，MPTP 诱导的 PD 大鼠表现出氧化应激和炎症增加，导致认知缺陷。此外，与对照和假手术动物相比，MPTP 诱导的 PD 大鼠的线粒体生物发生也减少。与 MPTP 诱导的 PD 大鼠相比，腹腔内给予 GW1929 和 α-硫辛酸的剂量低于文献中先前分别报道的剂量，可改善认知缺陷。这些改善伴随着氧化应激和炎症水平的降低。此外，还观察到这些药物联合使用后线粒体生物发生增加。
我们的结果为开发针对 PPARγ 和 PGC-1α 的药物提供了依据，这些药物可能是治疗 PD 等神经退行性疾病的有效治疗方法。
