Nicolakakis Nektaria, Hamel Edith
Laboratory of Cerebrovascular Research, Neurology and Neurosurgery, Montreal Neurological Institute, McGill University Montreal, QC, Canada.
Front Aging Neurosci. 2010 May 21;2. doi: 10.3389/fnagi.2010.00021. eCollection 2010.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (alpha, gamma, beta/delta), and synthetic ligands for PPARalpha (fibrates) and PPARgamma (Thiazolidinediones, TZDs) are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARgamma, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARgamma ligands in the treatment of brain disorders such as Alzheimer's disease (AD), leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARgamma agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.
过氧化物酶体增殖物激活受体（PPARs）是配体激活的核转录因子，可调节外周脂质和葡萄糖代谢。PPAR家族由三种亚型组成（α、γ、β/δ），目前用于治疗血脂异常和2型糖尿病的PPARα（贝特类药物）和PPARγ（噻唑烷二酮类药物，TZDs）的合成配体已获处方。与PPARs在外周的明确作用相反，直到最近人们对这些受体在脑和脑血管系统中的存在或功能仍知之甚少。事实上，过去十年的研究在大多数脑细胞类型中发现了这些受体，并表明它们的激活，尤其是PPARγ的激活，与正常脑和脑血管生理有关，并在病理条件下具有保护作用。值得注意的是，越来越多的证据突出了PPARγ配体在治疗阿尔茨海默病（AD）等脑部疾病方面的治疗潜力，从而促使在AD临床试验中对TZDs吡格列酮和罗格列酮进行测试。本综述将重点关注PPARγ激动剂对血管、神经元和神经胶质网络的益处，并根据转基因小鼠模型的证据和最近的临床试验评估这些化合物作为未来AD治疗药物的价值。
