Altered PPARγ expression and activation after transient focal ischemia in rats

Abstract

Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists troglitazone and pioglitazone reduce injury and inflammation in a rat model of transient cerebral ischemia. The mechanism of this protection is unclear, as these agents can act through PPAR-gamma activation or through PPAR-gamma-independent mechanisms. Therefore, we examined PPAR-gamma expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR-gamma antagonist, T0070907, to determine the role of PPAR-gamma during ischemia. Using immunohistochemical techniques and real-time PCR, we found low levels of PPAR-gamma mRNA and PPAR-gamma immunoreactivity in nonischemic brain; however, PPAR-gamma expression dramatically increased in ischemic neurons, peaking 24 h following middle cerebral artery occlusion. Interestingly, we found that in both vehicle- and agonist-treated brains, DNA binding was reduced in the ischemic hemisphere relative to the contralateral hemisphere. Expression of a PPAR-gamma target gene, lipoprotein lipase, was also reduced in ischemic relative to nonischemic brain. Both DNA binding and lipoprotein lipase expression were increased by the addition of the PPAR-gamma agonist rosiglitazone. Finally, we found that rosiglitazone-mediated protection after stroke was reversed by the PPAR-gamma antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR-gamma agonist, suggesting that endogenous PPAR-gamma ligands may mitigate the effects of cerebral ischemia.

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury

“…[4][5][6]27 MPO activity and levels of TNFa and IL-1b were significantly increased in the spinal cord tissue of injured rats compared with sham-operated animals 24 h after injury in the present study. In a finding similar to other studies, [17][18][19][20]24 rosiglitazone treatment significantly reduced these increased levels of MPO, TNFa and IL-1b in the present study, thus protecting the spinal cord against secondary degeneration caused by inFammation. It is thought that TZDs confer their neuroprotective effects via the prevention of both microglial activation and inFammatory cytokine/chemokine expression, 28 in concurrence with the findings of the present study.…”

“…15,16 The anti-inflammatory and antioxidant properties of rosiglitazone have been studied in models of central nervous system injury and disease, including amyotrophic lateral sclerosis, 17 Parkinson's disease 18 and cerebral ischaemia or haemorrhage. 19 Rosiglitazone has also been shown to prevent apoptosis in experimental traumatic brain injury. 20 The aim of the present study was to investigate the neuroprotective effects of rosiglitazone in a rat SCI model.…”

Microglial Activation in Stroke: Therapeutic Targets

“…172 Cerebral ischemia increases PPAR␥ expression in neurons and microglia, but at the same time DNA binding of PPAR␥ is reduced. 174 DNA binding is restored by PPAR␥ ligands, 170,174,175 and these agents have been shown to reduce ischemic injury in rodent stroke models. 176 Treatment with PPAR␥ ligands reduces microglia and macrophage activation and migration to the periinfarct regions, 177,178 attenuates the expression of ICAM-1, MMP-9, IL-1␤, COX-2, TNF␣, and iNOS, and suppresses production of reactive oxygen species.…”

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

“…Several animal studies have demonstrated the beneficial effects of TZDs in improving post-ischemic functional outcome. After focal ischemia, PPAR-gamma expression was observed to be increased in the brain, especially in the peri-infarct area, but surprisingly, its DNA-binding activity was reported to be reduced (15,37). Also, PPAR-gamma agonists trans-repress the transcription of downstream pro-inflammatory genes after ischemia (37) (Table 3).…”