The intracerebral application of the PPARγ‐ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain

Abstract

The present study addresses the neuroprotective function of intracerebroventricular (i.c.v.) application of pioglitazone, a selective ligand of the peroxisome proliferator-activated receptor gamma (PPARgamma) in the rat brain after ischaemia. Pioglitazone or vehicle were i.c.v. infused via osmotic minipumps over a 5-day period before, and 2 days after transient middle cerebral artery occlusion (MCAO) for 90 min. This i.c.v. application of pioglitazone in the brain significantly reduced the infarct size and brain oedema, and attenuated in the peri-infarct cortical regions the invasion of activated microglia and macrophages. Moreover, pioglitazone improved the recovery of sensory deficits 48 h after MCAO. Our data demonstrate for the first time that it is the activation of intracerebral PPARgamma that can confer neuroprotection, anti-inflammatory and neurological improvement following ischaemic injury.

Synthesis of Lipoxin A4by 5-Lipoxygenase Mediates PPARγ-Dependent, Neuroprotective Effects of Rosiglitazone in Experimental Stroke

“…These findings strongly suggest that the upregulation of 5-LO induced by rosiglitazone is beneficial and mediates the neuroprotective effect of rosiglitazone after MCAO. Anti-inflammatory mechanisms have been demonstrated to mediate the neuroprotective effects of PPAR␥ agonists (Pereira et al, 2005(Pereira et al, , 2006Sundararajan et al, 2005;Zhao et al, 2005;Collino et al, 2006;Luo et al, 2006;Zhao Y et al, 2006;Tureyen et al, 2007). Our present data confirm this mechanism of rosiglitazone, as shown by the inhibition of the expression of inflammatory genes with a deleterious role in cerebral ischemia, namely, COX-2, iNOS, MMP9 and TNF-␣.…”

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

“…Rosiglitazone pretreatment in both rats and mice also significantly decreased the infarct volume following focal ischemia and this effect was completely reversed when a specific PPAR-gamma-antagonist, GW9662 was administered prior to TZD treatment (33,37). Direct intracerebroventricular administration of pioglitazone for 5 days prior to and 2 days following ischemia also resulted in increased sensory neurologic scores compared to untreated controls accompanied by reduced infarct volume and edema (40). In another study, rats tube-fed with rosiglitazone for 7 days prior to and 3 days following transient focal ischemia showed increased endothelial nitric oxide synthase (eNOS) levels that correlated with increased angiogenesis and ischemic tolerance (46).…”

“…Several pre-conditioning experiments, where animals were either injected with TZDs or fed TZD-fortified diets, have shown significant neuroprotection when these animals were subjected to focal cerebral ischemia (15,40,41). In adult rodents, pre-treatment with rosiglitazone or pioglitazone one day prior to ischemia resulted in decreased microglial activation and macrophage infiltration, as well as decreased expression of proinflammatory COX2, iNOS and IL-1beta mRNA in the ischemic hemisphere (33,41).…”

Microglial Activation in Stroke: Therapeutic Targets

“…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. 177,179 …”