The PPAR-gamma agonist, darglitazone, restores acute inflammatory responses to cerebral hypoxia-ischemia in the diabetic ob/ob mouse.
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)-gamma 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 (30+/-13% to 3.3+/-1.6%, n=6 to 8) but did not show any significant effect in the ob/+ mice. Microglial and astrocytic activation monitored by cytokine expression (interleukin-1beta and tumor necrosis factor-alpha) 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.
Department of Neural and Behavioral Sciences, College of Medicine, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
Rashmi
R
Kumari
Lisa B
LB
Willing
Shyama D
SD
Patel
J Kyle
JK
Krady
William J
WJ
Zavadoski
E Michael
EM
Gibbs
Susan J
SJ
Vannucci
Ian A
IA
Simpson
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D017403:In Situ Hybridization; D007249:Inflammation / Q000276:immunology*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000187:drug effects; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008079:Lipoproteins, VLDL; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; C089948:darglitazone; D003345:Corticosterone