Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh PA, USA.
Prog Neurobiol. 2018 Apr-May;163-164:27-58. doi: 10.1016/j.pneurobio.2017.10.002. Epub 2017 Oct 12.
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.
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，它调节参与炎症、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的基因表达。合成的 PPARγ 激动剂（如噻唑烷二酮）用于治疗 2 型糖尿病，并有潜力通过减轻合并症的影响来限制中风等脑损伤的风险。如果发生脑损伤，PPARγ 作为细胞保护应激反应的主控门，通过抑制 NFκB 途径来限制组织损伤，从而提高细胞存活和内稳态平衡恢复的机会。在急性损伤阶段，PPARγ 通过抑制 NFκB 途径来减轻炎症，刺激 Nrf2/ARE 轴来中和氧化应激，直接限制组织损伤。在急性脑损伤的慢性阶段，受损细胞中 PPARγ 的激活导致灰质和白质的修复、血脑屏障的维持、神经血管单元的重建、炎症的消退以及长期功能的恢复。因此，PPARγ 处于细胞命运决定的顶点，并对急性损伤情况的慢性进展产生深远影响。在这里，我们综述了 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，并确定了它的靶基因。PPARγ 对炎症、代谢、细胞命运（增殖/分化/成熟/存活）以及许多其他过程的调节也与其他神经疾病有关。因此，PPARγ 是针对许多进行性神经疾病的治疗的一个有吸引力的靶点。
