Abstract: Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its clinical potential in the treatment of cognitive impairment in diseases such as Alzheimer’s disease (AD) and Parkinson disease (PD) is currently being explored. This review focused on the reported beneficial effects of pioglitazone on cognitive dysfunction and summarized the associated mechanisms associated with pioglitazone-induced improvement in cognitive dysfunction. Our review of the relevant literature indicated that there is conclusive evidence of the effect of pioglitazone on improving cognitive impairment via its agonistic effect on PPAR-γ. Further, several mechanisms of action have been reported, and these include enhanced NF-kB and p38 activity; regulation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α; inhibition of Aβ production; alterations in the levels of mitochondrial proteins such as mitoNEET; regulation of protein kinases such as CDK5 and JNK; regulation of ROS and MDA levels and the levels of the antioxidant proteins TRX1 and PON2; and increased expression of thyroid hormone receptors. Despite these promising findings, pioglitazone treatment is also associated with cardiovascular risks, such as weight gain and edema, which subsequently increase the risk of mortality. Further, it has been documented that pioglitazone may be unable to cross the blood–brain barrier when administered in certain forms, and it can also cause cell death when administered at high concentrations. Therefore, further research is required to explore the effects of acute and chronic pioglitazone treatment on memory function and the associated risks, in order to determine its clinical applicability in the treatment of cognitive disorders. Nonetheless, the current literature does demonstrate that pioglitazone promotes the function of PPAR receptors in ameliorating inflammation, oxidative stress, amyloidogenesis, and hypothyroidism, and enhancing neurogenesis, synaptic plasticity, and mitochondrial function. Therefore, these mechanisms of PPAR receptors warrant further investigation in order to establish the clinical applicability of pioglitazone in the treatment of cognitive disorders, such as PD and AD, and neuronal impairment in conditions such as diabetes.

Keywords: peroxisome proliferator-activated receptor gamma agonist, cognitive impairment, neuroinflammation, mitochondria


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吡格列酮对认知障碍的保护作用及其潜在机制：文献综述

摘要：吡格列酮是一种过氧化物酶体增殖物激活受体 γ (PPARγ) 激动剂，已知对大脑具有抗炎和抗氧化作用，其临床潜力可用于治疗阿尔茨海默病 (AD) 和目前正在探索帕金森病（PD）。本综述重点关注已报道的吡格列酮对认知功能障碍的有益作用，并总结了与吡格列酮诱导的认知功能障碍改善相关的相关机制。我们对相关文献的回顾表明，有确凿的证据表明吡格列酮通过其对 PPAR-γ 的激动作用来改善认知障碍。此外，已经报道了几种作用机制，其中包括增强的 NF-kB 和 p38 活性；调节促炎细胞因子 IL-1、IL-6 和 TNF-α；抑制 Aβ 的产生；线粒体蛋白水平的改变，如mitoNEET；调节蛋白激酶，如 CDK5 和 JNK；调节 ROS 和 MDA 水平以及抗氧化蛋白 TRX1 和 PON2 的水平；并增加甲状腺激素受体的表达。尽管有这些令人鼓舞的发现，吡格列酮治疗也与心血管风险相关，例如体重增加和水肿，这随后会增加死亡风险。此外，据记载，吡格列酮在以某些形式给药时可能无法穿过血脑屏障，并且在以高浓度给药时也会导致细胞死亡。所以，需要进一步研究探索急性和慢性吡格列酮治疗对记忆功能的影响和相关风险，以确定其在治疗认知障碍中的临床适用性。尽管如此，目前的文献确实证明了吡格列酮促进 PPAR 受体在改善炎症、氧化应激、淀粉样蛋白生成和甲状腺功能减退以及增强神经发生、突触可塑性和线粒体功能方面的功能。因此，PPAR 受体的这些机制值得进一步研究，以确定吡格列酮在治疗认知障碍（如 PD 和 AD）和神经元损伤（如糖尿病）中的临床适用性。以确定其在治疗认知障碍中的临床适用性。尽管如此，目前的文献确实证明了吡格列酮促进 PPAR 受体在改善炎症、氧化应激、淀粉样蛋白生成和甲状腺功能减退以及增强神经发生、突触可塑性和线粒体功能方面的功能。因此，PPAR 受体的这些机制值得进一步研究，以确定吡格列酮在治疗认知障碍（如 PD 和 AD）和神经元损伤（如糖尿病）中的临床适用性。以确定其在治疗认知障碍中的临床适用性。尽管如此，目前的文献确实证明了吡格列酮促进 PPAR 受体在改善炎症、氧化应激、淀粉样蛋白生成和甲状腺功能减退以及增强神经发生、突触可塑性和线粒体功能方面的功能。因此，PPAR 受体的这些机制值得进一步研究，以确定吡格列酮在治疗认知障碍（如 PD 和 AD）和神经元损伤（如糖尿病）中的临床适用性。并增强神经发生、突触可塑性和线粒体功能。因此，PPAR 受体的这些机制值得进一步研究，以确定吡格列酮在治疗认知障碍（如 PD 和 AD）和神经元损伤（如糖尿病）中的临床适用性。并增强神经发生、突触可塑性和线粒体功能。因此，PPAR 受体的这些机制值得进一步研究，以确定吡格列酮在治疗认知障碍（如 PD 和 AD）和神经元损伤（如糖尿病）中的临床适用性。

关键词：过氧化物酶体增殖物激活受体γ激动剂，认知障碍，神经炎症，线粒体