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Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair
Progress in Neurobiology ( IF 6.7 ) Pub Date : 2017-10-12 , DOI: 10.1016/j.pneurobio.2017.10.002
Wei Cai , Tuo Yang , Huan Liu , Lijuan Han , Kai Zhang , Xiaoming Hu , Xuejing Zhang , Ke-Jie Yin , Yanqin Gao , Michael V.L. Bennett , Rehana K. Leak , Jun Chen

Peroxisome proliferator-activated receptor γ (PPARγ) is a widely expressed ligand-modulated transcription factor that governs the expression of genes involved in inflammation, redox equilibrium, trophic factor production, insulin sensitivity, and the metabolism of lipids and glucose. Synthetic PPARγ agonists (e.g. thiazolidinediones) are used to treat Type II diabetes and have the potential to limit the risk of developing brain injuries such as stroke by mitigating the influence of comorbidities. If brain injury develops, PPARγ serves as a master gatekeeper of cytoprotective stress responses, improving the chances of cellular survival and recovery of homeostatic equilibrium. In the acute injury phase, PPARγ directly restricts tissue damage by inhibiting the NFκB pathway to mitigate inflammation and stimulating the Nrf2/ARE axis to neutralize oxidative stress. During the chronic phase of acute brain injuries, PPARγ activation in injured cells culminates in the repair of gray and white matter, preservation of the blood-brain barrier, reconstruction of the neurovascular unit, resolution of inflammation, and long-term functional recovery. Thus, PPARγ lies at the apex of cell fate decisions and exerts profound effects on the chronic progression of acute injury conditions. Here, we review the therapeutic potential of PPARγ in stroke and brain trauma and highlight the novel role of PPARγ in long-term tissue repair. We describe its structure and function and identify the genes that it targets. PPARγ regulation of inflammation, metabolism, cell fate (proliferation/differentiation/maturation/survival), and many other processes also has relevance to other neurological diseases. Therefore, PPARγ is an attractive target for therapies against a number of progressive neurological disorders.



中文翻译:

过氧化物酶体增殖物激活受体γ(PPARγ):CNS损伤和修复的主要看门人

过氧化物酶体增殖物激活受体γ(PPARγ)是一种广泛表达的配体调节转录因子,它控制与炎症,氧化还原平衡,营养因子产生,胰岛素敏感性以及脂质和葡萄糖代谢有关的基因的表达。合成的PPARγ激动剂(例如。噻唑烷二酮类药物可用于治疗II型糖尿病,并有可能通过减轻合并症的影响来限制发生脑中风(如中风)的风险。如果发生脑损伤,PPARγ可以作为细胞保护性应激反应的主要看门人,从而提高细胞存活率和体内平衡状态的恢复机会。在急性损伤阶段,PPARγ通过抑制NFκB途径来减轻炎症并刺激Nrf2 / ARE轴来中和氧化应激,从而直接限制组织损伤。在急性脑损伤的慢性期,受伤细胞中的PPARγ活化最终达到灰白物质的修复,血脑屏障的保存,神经血管单位的重建,炎症的消退和长期功能恢复。因此,PPARγ是决定细胞命运的最高点,对急性损伤条件的慢性发展具有深远的影响。在这里,我们回顾了PPARγ在中风和脑外伤中的治疗潜力,并强调了PPARγ在长期组织修复中的新作用。我们描述了它的结构和功能,并确定了它靶向的基因。PPARγ对炎症,新陈代谢,细胞命运(增殖/分化/成熟/存活)和许多其他过程的调节也与其他神经系统疾病有关。因此,PPARγ是针对许多进行性神经系统疾病的治疗的有吸引力的靶标。我们回顾了PPARγ在中风和脑外伤中的治疗潜力,并强调了PPARγ在长期组织修复中的新型作用。我们描述了它的结构和功能,并确定了它靶向的基因。PPARγ对炎症,新陈代谢,细胞命运(增殖/分化/成熟/存活)和许多其他过程的调节也与其他神经系统疾病有关。因此,PPARγ是针对许多进行性神经系统疾病的治疗的有吸引力的靶标。我们回顾了PPARγ在中风和脑外伤中的治疗潜力,并强调了PPARγ在长期组织修复中的新型作用。我们描述了它的结构和功能,并确定了它靶向的基因。PPARγ对炎症,新陈代谢,细胞命运(增殖/分化/成熟/存活)和许多其他过程的调节也与其他神经系统疾病有关。因此,PPARγ是针对许多进行性神经系统疾病的治疗的有吸引力的靶标。

更新日期:2017-10-12
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