GW1929: A nonthiazolidinedione PPARγ agonist, ameliorates neurological damage in global cerebral ischemic-reperfusion injury through reduction in inflammation and DNA fragmentation

Transient global cerebral ischemia results in acute neurodegeneration in selective brain areas. Global cerebral ischemic-reperfusion (IR) injury induced selective hippocampal damage results into various neurobehavioral deficits including spatial memory and learning deficiencies. In this study, we have investigated the protective effects of a nonthiazolidinedione PPAR gamma agonist. N-(2-benzoylphenyl)-O[2-(methyl-2-pyridinylamino)ethyl]-L-tyrosine (GW1929), against global cerebral IR injury induced neurobehavioral deficits and brain damage in gerbils. Bilateral carotid artery occlusion induced global cerebral ischemia in gerbils resulted in neurological deficits, hyperlocomotion, reduced response latency in passive avoidance test and hippocampal damage. Hippocampal neurodegeneration after cerebral IR injury was also associated with significant increase in iNOS and MMP-9 immunoreactivity along with TNF alpha and IL-6 levels. Massive apoptotic DNA fragmentation as evident from increased TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labelling)-positive cells was also observed in the CA1 hippocampal region of IR challenged gerbils. GW1929 treatment significantly ameliorated cerebral IR induced neurological symptoms, hyperlocomotion, cognitive deficits and hippocampal neuronal damage in CA1 hippocampus region in gerbils. Significant reduction in IR injury induced iNOS and MMP-9 immunoreactivity, TNF alpha and IL-6 levels and apoptotic DNA fragmentation was also observed with GW1929 treatment. Pioglitazone, thiazolidinedione PPAR gamma agonist also exhibited similar effects on inflammatory parameters after global cerebral IR injury. In summary, this study demonstrates neuroprotective effects of GW1929 in global cerebral IR injury induced neurobehavioral deficits and brain pathology which may be attributed to reduced inflammation and apoptotic DNA fragmentation, suggesting therapeutic potential of PPAR gamma agonists in cerebral IR injury. (C) 2010 Elsevier B.V. All rights reserved.