A14156 Amelioration of Ischemic Brain Injury by Angiotensin II Type 2 Receptor Stimulation via Peroxisome Proliferator-Activated Receptor-gamma Activation

Abstract

Objectives: The brain renin-angiotensin system plays a crucial role in ischemic brain damage. It is well known that stimulation of the angiotensin II type 2 (AT2) receptor protects against ischemic brain injury. Our recent data showed that AT2 receptor stimulation by compound 21 (C21), a direct AT2 receptor agonist, inhibited vascular intimal proliferation by activating peroxisome proliferator-activated receptor-gamma (PPAR-γ). Therefore, we examined the possibility that direct AT2 receptor stimulation by C21 has protective effect against ischemic brain injury via PPAR-γ activation. Methods: Eight-week-old male C57BL/6J mice were subjected to permanent middle cerebral artery (MCA) occlusion. They were pretreated by C21 with or without GW9662, a PPAR-γ antagonist, for two weeks. Neurologic deficit, ischemic size, superoxide anion production, superoxide dismutase (SOD) activity and expression of NADPH subunits were assessed 24 hours after MCA occlusion. Cerebral blood flow (CBF) was monitored in the core and periphery of the MCA territory before, immediately after, 1 hour and 24 hours after MCA occlusion. Results: The change of blood pressure was not detected in each group. Treatment with C21 significantly decreased the neurologic deficit and ischemic size with increases in CBF and SOD activity, and a decrease of superoxide anion production compared with the non-treated group. Co-administration of GW9662 partially attenuated such effect of C21 on ischemic size by inhibiting the decreased superoxide anion production and increased CBF and SOD activity. Conclusion: These results suggested that direct AT2 receptor stimulation by C21 had a beneficial effect on stroke-induced brain injury partly due to PPAR-γ activation.