gw9662 and Brain-Injuries

PPARγ has been reported to participate in intracerebral hemorrhage (ICH) progression, and recruit RAD21 through binding DNA. Our study aimed to explore the roles of PPARγ/RAD21 in ICH and their related mechanisms.. ICH models in vitro and in vivo were established using thrombin and autologous blood injection, respectively. After that, rosiglitazone (RSG), GW9662, and RAD21 knockdown/overexpression plasmids were used to treat the ICH models. The cell apoptosis, the related inflammatory cytokines levels, and the neurological function of the rats were examined. Real-time quantitative PCR (RT-qPCR), western blot and immunofluorescence were employed to determine the expression of the M1/M2 polarization-related markers. Finally, the interaction of PPARγ and RAD21 in microglial cells was observed using double labeled immunofluorescence and co-immunoprecipitation.. After thrombin induction, the cell apoptosis, and TNF-α, IL-1β and IL-10 contents were all significantly increased (P < 0.05); whereas RSG and RAD21 overexpression evidently inhibited the apoptosis of thrombin-caused microglial cells, reduced TNF-α and IL-1β contents, further increased IL-10 content (P < 0.05). The combination of RAD21 and PPARγ was enhanced by RSG and RAD21 overexpression. In vivo experiments showed that RSG and RAD21 overexpression decreased neurological deficit score, brain water content and hematoma volume. Additionally, RSG and RAD21 overexpression up-regulated the expression of PPARγ, RAD21, Arg1, KLF4, and TGF-β, whereas down-regulated iNOS and CD32 expression. The actions of GW9662 and RAD21 knockdown were opposite to those of RSG and RAD21 overexpression.. PPARγ/RAD21 may alleviate ICH progression through promoting M2-type polarization of microglial cells and inhibiting inflammatory response.

Topics: Animals; Brain Injuries; Brain Neoplasms; Cerebral Hemorrhage; Interleukin-10; Microglia; PPAR gamma; Rats; Rosiglitazone; Thrombin; Tumor Necrosis Factor-alpha

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-activated transcription factor of nuclear hormone receptor superfamily. Thiazolidinedione rosiglitazone is a potent agonist of PPARgamma which was shown to induce neuroprotection in animal models of focal ischemia and spinal cord injury. We currently evaluated the therapeutic potential of rosiglitazone (6 mg/kg at 5 min, 6 h and 24 h; i.p.) following controlled cortical impact (CCI)-induced traumatic brain injury (TBI) in adult mice. CCI injury increased the cortical PPARgamma mRNA levels which were further elevated by rosiglitazone treatment. In addition, rosiglitazone treatment significantly decreased the cortical lesion volume measured at 7 days compared to vehicle treatment (by 56+/-7%; p<0.05; n=6/group). Following TBI, the spared cortex of the rosiglitazone group showed significantly less numbers of GSI-B4(+) activated microglia/macrophages and ICAM1(+) capillaries, and curtailed induction of pro-inflammatory genes IL6, MCP1 and ICAM1 compared to vehicle group. Rosiglitazone-treated mice also showed significantly less number of TUNEL(+) apoptotic neurons and curtailed induction of caspase-3 and Bax, compared to vehicle control. In addition, rosiglitazone significantly enhanced the post-TBI expression of the neuroprotective chaperones HSP27, HSP70 and HSP32/HO1, and the anti-oxidant enzymes catalase, Cu/Zn-SOD and Mn-SOD, compared to vehicle. Treatment with GW9662 (a specific PPARgamma antagonist) prevented all the above PPARgamma-mediated actions. Thus, PPARgamma activation confers neuroprotection after TBI by anti-inflammatory, anti-apoptotic and anti-oxidative mechanisms.

Topics: Analysis of Variance; Anilides; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blotting, Western; Brain Injuries; Cerebral Cortex; Gene Expression; HSP27 Heat-Shock Proteins; Hypoglycemic Agents; In Situ Nick-End Labeling; Injections, Intraperitoneal; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; Rosiglitazone; Superoxide Dismutase; Thiazolidinediones