Activation of Peroxisome Proliferator-Activated Receptor-gamma Protects against White Matter Injury in Immature Mice Brain

• Main Authors: Li-yen Chong, 張麗嫣
• Other Authors: Chao-Ching Huang
• Format: Others
• Language: en_US
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/40955632868606123302

碩士 === 國立成功大學 === 生物化學研究所 === 97 === Up to 25% of preterm survivors have cerebral palsy and cognitive deficits. The underlying pathology for cerebral palsy in the premature infants is periventricular leukomalacia (PVL), a developmental lesion of the deep cerebral white matter. Vascular immaturity, inflammation and apoptosis are major pathogenesis factors of PVL. Animal experiments have shown that activation of peroxisome proliferator activated receptor (PPAR)-gamma, a key regulator of glucose and fat metabolism, effectively attenuated neurodegenerative and the inflammatory processes in adult brain. Thus, we hypothesized that activation of PPAR-gamma protects against white matter injury (WMI), on the contrary, PPAR-gamma gene deficiency exacerbates WMI in neonatal brain. We found that pre-treatment with a PPAR-gamma agonist, rosiglitazone (3 mg/kg in 25% of DMSO), significantly attenuated hypoxic ischemia injury in the white matter and hippocampus (P<0.05). The rosiglitazone-mediated protection in the white matter was associated with attenuation of activated microglia, TNF-alpha expression, extravasation of IgG and activated caspase-3 (+) cells after hypoxic ischemia. PpargP465L/+ mice, which harbor an allele with dominant negative mutant in PPAR-gamma, showed exacerbated WMI than wild-type pups (P<0.05). Moreover, HI-induced microglia activation and upregulation of TNF-alpha, extravasation of IgG and activated caspase-3 (+) cells were enhanced in PpargP465L/+ mice than in wild-type pups 24 hours after hypoxic ischemia. In summary, activation of PPAR-gamma protects against WMI, while PPAR-gamma deficiency worsens WMI by enhancing neuroinflammation, blood-brain barrier damage and cell apoptosis after hypoxic ischemia. These findings suggest that PPAR-gamma agonists are attractive therapeutic targets for treating WMI in neonatal brain.