1. ¹Department of Neural and Behavioral Sciences, College of Medicine, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, USA
2. ²Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research & Development, Groton, Connecticut, USA
3. ³Department of Pediatrics/Newborn Medicine, Weill Cornell Medical College, New York, New York, USA

Correspondence: Dr IA Simpson, Department of Neural and Behavioral Sciences, College of Medicine, Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033, USA. E-mail: ixs10@psu.edu

Received 18 June 2009; Revised 10 September 2009; Accepted 18 September 2009; Published online 28 October 2009.

Abstract

Diabetes is an increased risk factor for stroke and results in increased brain damage in experimental animals and humans. The precise mechanisms are unclear, but our earlier studies in the db/db mice suggested that the cerebral inflammatory response initiating recovery was both delayed and diminished in the diabetic mice compared with the nondiabetic db/+ mice. In this study, we investigated the actions of the peroxisome proliferator-activated receptor (PPAR)- agonist darglitazone in treating diabetes and promoting recovery after a hypoxic-ischemic (H/I) insult in the diabetic ob/ob mouse. Male ob/+ and ob/ob mice received darglitazone (1 mg/kg) for 7 days before induction of H/I. Darglitazone restored euglycemia and normalized elevated corticosterone, triglycerides, and very-low-density lipoprotein levels. Darglitazone dramatically reduced the infarct size in the ob/ob mice at 24 h of recovery compared with the untreated group (3013% to 3.31.6%, n=6 to 8) but did not show any significant effect in the ob/+ mice. Microglial and astrocytic activation monitored by cytokine expression (interleukin-1 and tumor necrosis factor-) and in situ hybridization studies (bfl1 and glial fibrillary acidic protein) suggest a biphasic inflammatory response, with darglitazone restoring the compromised proinflammatory response(s) in the diabetic mouse at 4 h but suppressing subsequent inflammatory responses at 8 and 24 h in both control and diabetic mice.