FPS-ZM1 Alleviates Neuroinflammation in Focal Cerebral Ischemia Rats via Blocking Ligand/RAGE/DIAPH1 Pathway

• DOI: 10.1021/acschemneuro.0c00530
• Publication Date: 2020-12-10T21:19:28Z
• Authors: Lingling Shen; Tianyuan Zhang; Yu Yang; Dan Lu; Anding Xu; Keshen Li
• Keywords: RAGE; Proinflammatory cytokine

Receptor for advanced glycation end products (RAGEs), a multiligand receptor belonging to the cell-surface immunoglobulin superfamily, has been reported play crucial role in neuroinflammation and neurodegenerative diseases. Here, we tested our hypothesis that RAGE-specific antagonist FPS-ZM1 is neuroprotective against ischemic brain injury. Distal middle cerebral artery occlusion (MCAO) or sham operation was performed on anesthetized Sprague-Dawley male rats (n = 60), which were then treated with vehicle (four groups total Vehicle + MCAO, sham, sham). After 1 week, neurological function evaluated, then, tissues collected 2,3,5-triphenyltetrazolium chloride staining, Nissl TUNEL Western blotting, immunohistochemical analyses. treatment after MCAO markedly attenuated deficits reduced infarct area. More interestingly, inhibited ischemia-induced astrocytic activation microgliosis decreased elevated levels of proinflammatory cytokines. Furthermore, blocked increase level RAGE and, notably, DIAPH1, key cytoplasmic hub RAGE-ligand-mediated cellular signaling. Accordingly, also reversed MCAO-induced phosphorylation NF-κB targets are potentially downstream from RAGE/DIAPH1. Our findings reveal reduces focal ischemia further suggest ligand/RAGE/DIAPH1 pathway contributes this FPS-ZM1-mediated alleviation neuroinflammation.