Potential Role Of PPAR-gamma Agonist Rosiglitazone In Cerebral Vasospasm After Subarachnoid Hemorrhage Model

PART I:Peroxisome proliferator-activated receptor gamma agonist rosiglitazone attenuates oxyhemoglobin-induced Toll-like receptor 4 expression in vascular smooth muscle cellsInflammation and immune response have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Recently, increased TLR4 expression has been associated with the development of cerebral vasospasm in a rabbit model of SAH. Peroxisome proliferator-activated receptor gamma (PPARy) aonists, effective inhibitors of TLR4 activation, may modulate the vasospasm progression via their anti-inflammation effects. We investigate whether the blood component oxyhemoglobin (OxyHb) can induce the expression of Toll-like receptor (TLR) 4 in vacular smooth muscle cells (VSMCs), and evaluate the modulatory effects of PPARy agonist rosiglitazone on OxyHb-induced inflammation in VSMCs. Cultured VSMCs incubated with or without rosiglitazone were exposed to OxyHb at 10?M for up to 48 h. Expression of TLR4 was assessed by immunocytochemistry and Western blot analysis. Production of tumor necrosis factor a (TNF-a) in conditioned medium were quantified by ELISA. A marked increase of TLR4 production and TNF-a release was observed at 48 h after cells treated with OxyHb. Rosiglitazone reduced TLR4 immunocytochemistry staining and protein production significantly in VSMCs. A specific antagonist for PPARy, GW9662, could reverse the anti-inflammatory effects of rosiglitazone. The results demonstrated that OxyHb exposure could induced TLR4 activation in cultured VSMCs. Rosiglitazone suppressed TLR4 expression and cytokine release via the activation of PPARy and may have therapeutic potential for the treatment of vasospasm following SAH.PART?:Therapeutic potential of PPAR-gamma agonist rosiglitazone in cerebral vasospasm after a rat experimental subarachnoid hemorrhage modelThe pathogenesis of cerebral vasospasm is closely associated with inflammation and immune response in arterial walls. Rencently, the authors proved the key role of Toll-like receptor (TLR)4 in the development of vasospasm in experimental subarachnoid hemorrhage (SAH) model. Because peroxisome proliferator-activated receptor (PPAR) gamma aonists are identified as effective inhibitors of TLR4 activation, we investigated the anti-inflammation properties of PPAR-gamma agonist rosiglitazone in basilar arteries in a rat experimental SAH model and evaluated the effects of rosiglitazone on vasospasm. A total of 78 male rats were randomly divided into three groups:control group (n=26), SAH group (SAH+vehicle, n=26), rosiglitazone group (SAH+rosiglitazone, n=26). All SAH animals were subjected to injection of 0.2ml autologous blood into cisterna magna twice on day 0 and day 1. Rosiglitazone or equal volumes of DMSO (Vehicle for rosiglitazone) was administrated intraperitoneally (3mg/kg) at 30 min before surgery plus 30 min after SAH induction, respectively. After 24 h, the same administration was repeated. The basilar arteries and hippocampus were harvested on day 5 after SAH. Inflammatory responses in basilar arteries were assessed by immunohistochemical stainning for intercellular molecule (ICAM)-l and myeloperoxidase (MPO). Inflammatory responses in hippocampus were evaluated by immunohistochemical stainning for ED-1 (a probe for dectecting active microglia). Expression of TLR4 was determined by western blot analysis. The degree of cerebral vasospasm was evaluated by measuring the mean diameter and cross-sectional area of basilar arteries. Rosiglitazone suppressed the SAH-induced inflammatory responses in basilar arteries and hippocampus by inhibiting the TLR4 signalling. Furthermore, rosiglitazone could attenuate cerebral vasospasm following SAH. Therefore, we suggested that PPAR-gamma agonists may be potential therapeutic agents for cerebral vasospasm and brain injury after SAH.