Abstract WP159: FPS-ZM1 Alleviates Neuroinflammation in Focal Cerebral Ischemia Rats via Blocking the RAGE/DIAPH1/NF-kappa B Pathway

Abstract

Introduction: The receptor for advanced glycation end-products (RAGE), belonging to the cell surface immunoglobulin superfamily, is a multi-ligands receptor. It is reported that RAGE plays a crucial role in neuroinflammation and neurodegeneration diseases. Objective: In this study, we investigate the pathophysiological effect of RAGE and the therapeutically effect of its specific antagonist FPS-ZM1 in focal cerebral ischemia rats to provide an experimental evidence for the future clinical translational research. Methods: Sprague-Dawley male rats were anesthetized to receive the permanent middle cerebral artery occlusion (MCAO) or sham operation. After the operation, four groups of rats, the MCAO+vehicle, MCAO+FPS-ZM1, sham+vehicle and sham+FPS-ZM1 groups, were treated with FPS-ZM1 or vehicle as indicated above. One week later, neurological function was evaluated and then brain tissues were collected, along with 2,3,5-triphenyltetrazolium chloride staining, Nissl staining, TUNEL staining, Western blot and immunohistochemistry. Results: Treatment with FPS-ZM1 significantly attenuated the neurological deficit and reduced the infarct areas and necrotic neurons number. More interestingly, FPS-ZM1 decreased the ischemia-induced elevated levels of pro-inflammatory cytokines, inhibited the cell apoptosis and prevented the deposition of amyloid-beta and advanced glycation end products. FPS-ZM1 blocked the increase in RAGE levels and specifically, in levels of DIAPH1, the key cytoplasmic hub for RAGE ligand-mediated activation of cellular signaling. Downstream of RAGE/ DIAPH1, the increase in the protein level of phosphorylated NF-kappa B was also reversed by FPS-ZM1 in focal cerebral ischemia rats. Conclusion: These results illuminate that FPS-ZM1 treatment reduce neuroinflammation in focal cerebral ischemia rats and suggest that the RAGE/DIAPH1/NF-kappa B signaling pathway may contribute to alleviation of neuroinflammation by FPS-ZM1 in focal cerebral ischemia rats.