Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage

Abstract

Inflammation is a known precipitator of neuronal death after cerebral ischemia. The mechanisms that promote or curtail the start and spread of inflammation in brain are still being debated. By virtue of their capability to modulate gene expression, several transcription factors induced in the ischemic brain can modulate the post-ischemic inflammation. While the induction of transcription factors such as IRF1, NF-kappaB, ATF-2, STAT3, Egr1 and C/EBPbeta is thought to promote post-ischemic inflammation, activation of transcription factors such as HIF-1, CREB, c-fos, PPARalpha, PPARgamma and p53 is thought to prevent post-ischemic inflammation and neuronal damage. Of these, PPARgamma which is a ligand-activated transcription factor was recently shown to prevent inflammatory gene expression in several animal models CNS disorders. This review article discusses some of the molecular mechanisms of PPARgamma induction by its agonists following focal cerebral ischemia.

Figure 1

PPARγ gene organization (A) and a simplified representation of action of PPAR:RXR heterodimer and ligands in transcriptional process (B). Under the presence of ligands, corepressor is released from PPAR:RXR heterodimer, enabling it to bind to to cofactor HAT complex. With further recruitment of general transcription complexes, transcription process can resume. AF-1; activation function-1. DBD; DNA binding domain. LBD; ligand binding domain. D; hinge domain linking DBD and LBD. PPRE; peroxisome proliferator activated receptor responseive element. HAT; histone acetyltransferase.