PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury.
PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury.
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DOI：
10.1177/1753944708090924
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发表时间：
2008-06-01
影响因子：
2.3
通讯作者：
Thiemermann, Christoph
中科院分区：
文献类型：
--
作者：
Collino, Massimo;Patel, Nimesh S A;Thiemermann, Christoph
在工业化国家，中风是导致死亡和长期残疾的主要原因。尽管在了解其病理生理方面取得了进展，但在中风的治疗方面进展甚微。目前可用的治疗方法已被证明是非常不令人满意的（除了溶栓），并且正在尝试识别和表征可用于设计新的治疗方式的信号蛋白。过氧化物酶体增殖体激活受体（PPARs）是配体激活的转录因子，控制脂质和葡萄糖代谢。PPAR通过与类视黄醇X受体（RXR）结合，作为异源二聚体伴侣与特定的DNA序列结合，调节基因表达，称为PPAR反应元件。此外，ppar还可以通过不依赖dna结合的方式直接干扰其他转录因子通路来调节基因转录。迄今为止，已经确定了三种不同的PPAR异构体，分别为α， β / δ和γ。近年来，人们发现ppar在各种中枢神经系统疾病的发病机制中发挥着重要作用，越来越多的数据表明ppar可能是治疗缺血性脑卒中的潜在靶点。在一些体外和体内模型中，所有PPAR亚型的激活，尤其是PPAR γ亚型的激活，都被证明可以预防缺血后炎症和神经元损伤，并负向调节缺血/再灌注（I/R）诱导的基因表达。本文综述了ppar激动剂在脑I/R损伤治疗中的潜在治疗作用的证据和最新进展。
Stroke is a leading cause of death and long-term disability in industrialized countries. Despite advances in understanding its pathophysiology, little progress has been made in the treatment of stroke. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signaling proteins which could be exploited to design novel therapeutic modalities. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. PPARs regulate gene expression by binding with the retinoid X receptor (RXR) as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated alpha, beta/delta, and gamma, have been identified. Recently, they have been found to play an important role for the pathogenesis of various disorders of the central nervous system and accumulating data suggest that PPARs may serve as potential targets for treating ischemic stroke. Activation of all PPAR isoforms, but especially of PPARgamma, was shown to prevent post-ischemic inflammation and neuronal damage in several in vitro and in vivo models, negatively regulating the expression of genes induced by ischemia/ reperfusion (I/R). This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPAR-agonists in the treatment of cerebral I/R injury.