Neuroprotection against focal ischemic brain injury by the peroxisome proliferator‐activated receptor‐γ agonist rosiglitazone

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR-c) is a nuclear membrane-associated transcription factor that governs the expression of various inflammatory genes. PPAR-c agonists protect peripheral organs from ischemic injury. In the present study, we investigated whether the PPAR-c agonist rosiglitazone is neuroprotective against focal ischemic brain injury. C57/B6 mice underwent 1.5-h middle cerebral artery occlusion, and received either vehicle or rosiglitazone treatment of 0.75, 1.5, 3, 6 or 12 mg/kg (n ¼ 9 per group). Cerebral infarct volume, neurological function, expression of proinflammatory proteins and neutrophil accumulation were assessed after ischemia and reperfusion. At 48 h after ischemia, infarct volume was significantly decreased with 3-12 mg/kg of rosiglitazone, with a time window of efficacy of 2 h after ischemia at the optimal dose (6 mg/kg). Neutrophil accumulation was significantly decreased in the brain parenchyma of rosiglitazone-treated mice. Ischemia-induced expression of several inflammatory cytokines and chemokines was markedly reduced in rosiglitazone-treated brains, as determined using proteomic-array analysis. Rosiglitazone treatment improved neurological function at 7 days after ischemia. Moreover, in cultured cortical primary microglia, rosiglitazone attenuated inflammatory responses by decreasing lipopolysaccharide-induced release of tumor necrosis factor-a, interleukin (IL)-1b and IL-6. These results suggest that the PPAR-c agonist rosiglitazone has neuroprotective properties that are at least partially mediated via anti-inflammatory actions, and is thus a potential novel therapeutic agent for stroke.

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-␣.…”

Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

“…Recent studies have shown that both rosiglitazone and pioglitazone are neuroprotective in animal models of acute focal ischemia. 3 Studies have also shown that neuroprotection by TZDs following ischemia may involve: (a) a reduction in the inflammatory response, such as by upregulation of nuclear factor-kB, intercellular adhesion molecule-1, or cyclooxygenase; [16][17][18][19] (b) activation of an anti-inflammatory mediator, such as synthesis of lipoxin A 4 by 5-lipoxygenase expression; 20 (c) activation of superoxide dismutase; 21,22 or (d) prevention of harmful neuronal responses to ischemic insult, such as enhanced 14-3-3e expression. 23 There is significant evidence from these studies that PPARg activation is involved in neuroprotection.…”

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.…”