Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair

Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma 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, PPAR gamma 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, PPAR gamma directly restricts tissue damage by inhibiting the NFKI3 pathway to mitigate inflammation and stimulating the Nrf2/ARE axis to neutralize oxidative stress. During the chronic phase of acute brain injuries, PPAR gamma 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, PPAR gamma 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 PPAR gamma in stroke and brain trauma and highlight the novel role of PPAR gamma in long-term tissue repair. We describe its structure and function and identify the genes that it targets. PPAR gamma regulation of inflammation, metabolism, cell fate (proliferation/differentiation/maturation/survival), and many other processes also has relevance to other neurological diseases. Therefore, PPAR gamma is an attractive target for therapies against a number of progressive neurological disorders. (C) 2018 Elsevier Ltd. All rights reserved.