Abstract 651: PPARg and Intracerebral Hemorrhage
No medical or surgical therapy to date has been approved to significantly reduce morbidity or mortality after Intracerebral hemorrhage (ICH). Even in the patients who survive the ictus, the resulting hematoma within the brain triggers a series of events leading to secondary insults and severe neurological deficits. Hematoma absorption is a process of activated phagocytes to engulf the damaged and dead tissue, then leave the site and permit new tissue to fill the wound. Phagocytosis allows the non-inflammatory clearance of dead and dying cells. If we could remove the dislocated blood components timely and efficiently before they undergo lysis and spillage of toxic material by phagocytosis, then we could provide better protection to other brain parenchyma cells. Systematical administration of rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) significantly promoted hematoma resolution and improved functional recovery in a mice ICH model. The microglia isolated from rat/mice brains showed higher phagocytosis rate and capacity when treated with 15d-PGJ2, an endogenous PPARγ agonist. 15d-PGJ2 or rosiglitazone significantly up-regulated expression of two PPARγ-regulated genes (anti-oxidant gene-catalase and macrophage scavenger receptor gene-CD36), while downregulated the expression of pro-inflammatory intermediators in vivo and in vitro. Inhibiting PPARγ by GW9662, an PPARγ antagonist, or knockdown PPARγ by using the Cre-LoxP system in microglia significantly counteracted the effects of 15d-PGJ2 in promoting phagocytosis or in inhibiting generation of pro-inflammatory genes. Blocking PPARγ in microglia by intracellular delivery anti-PPARγ antibody significantly inhibited the neuroprotective effects of 15d-PGJ2 upon PPARγ activation during phagocytosis. Therefore, PPARγ activation in microglia may promote phagocytosis and hematoma absorption after ICH by
upregulating the expression of anti-oxidant enzymes and the scavenger receptor;
down-regulating expression of NF-κB-controlled proinflammatory intermediators.
PPARγ in microglia/ macrophage may act an anti-inflammatory factor to promote hematoma absorption and protect other brain cells from inflammation-mediated injury after ICH.