Indian Journal of Experimental Biology Vol. 48, August 2010, pp. 793-799 Neuroprotective effect of pioglitazone on acute phase changes induced by partial global cerebral ischemia in mice Bikash Medhi*, Raman Aggarwal & Amitava Chakrabarti Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India Received 22 October, 2009; revised 15 March 2010 Present study was carried out to investigate the possible neuroprotective effect of pioglitazone, an antidiabetic agent, peroxisome proliferator-activated receptor γ (PPARγ) agonist on acute phase changes in mice model of cerebral ischemia induced by Bilateral Common Carotid artery Occlusion (BCCAO). BCCAO model was used to induce partial global cerebral ischemia. BCCAO induced significant brain infarct size and edema in saline treated control group along with high increase in oxidative stress showed by increase lipid peroxidation and decreased levels of antioxidants like superoxide superoxide dismutage, catalase, glutathione peroxidase. Pioglitazone (20 mg/kg, orally) administration showed neuroprotective effects by reducing cerebral infarct size significantly as compared to control group. Postischemic seizure susceptibility was also reduced as number of positive responders decreased to a significant number. Brain edema was subsided to a significant level. Pioglitazone reduced the plasma TNF- α levels as compared to ischemia group significantly. Pioglitazone treatment also improved all the antioxidants levels showing activity against oxidative stress induced by BCCAO. Pioglitazone showed neuroprotection against ischemic insult suggesting the role of PPAR γ agonist in neuroprotective agents. Keywords: Cerebral ischemia, Pioglitazone, PPAR- γ, Neuroprotection Partial global cerebral ischemia (ischemia of forebrain and sub-cortical tissue) is a syndrome characterized by rapid onset of neurological injury due to interruption of blood flow to the brain 1,2 and it leads to various pathophysiological modalities such as ROS, calcium overload, mitochondrial damage, neuronal cell death etc. Global cerebral ischemia results in neuronal death irrespective of postischemic reperfusion 3 . Reperfusion after cerebral ischemia further adds to the complications of stoke by releasing various mediators such as proinflammatory cytokines and free radical generation. This increases the oxidative stress to the brain and ultimately leading to neuronal cell death. Seizures can occur soon after the onset of ischemia or can be delayed 4 . Seizure threshold decreases subsequently with ischemia and reperfusion injury. Repeated seizure-like activity in the setting of cerebral ischemia significantly increases infarct size and can impair functional recovery, an effect that can be ameliorated with the administration of certain neuroprotective agents 5-7 . Cerebral ischemia is frequently accompanied by inflammation, which can worsen neuronal injury. Activation of peroxisome proliferator-activated receptor γ (PPARγ) reduces inflammation and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In addition, PPAR γ activators increase levels of Cu-Zn-superoxide dismutase (SOD) in cultured endothelium, suggesting an additional mechanism by which it may exert protective effects within the brain 8 . Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcriptional regulators of genes controlling lipid and glucose metabolism 9 . These receptors have so far not been studied in ischemia reperfusion associated changes in whole body behavior or biochemical parameters in mice model. Therefore it was thought prudent to investigate the effects of in vivo administration pioglitazone on ischemia and reperfusion induced cerebral injury along with roles of PPAR γ activators in ischemia induced seizure susceptibility, behavioral defects and biochemical changes in model of partial global cerebral ischemia in mice. —————— *Correspondent author Telephone: + 91-172-2755250 (o); +91-9815409652(m) Fax : + 91-172-2744401, 172-2745078 E-mail: drbikashus@yahoo.com