1. Academic Validation
  2. FPS-ZM1 Alleviates Neuroinflammation in Focal Cerebral Ischemia Rats via Blocking Ligand/RAGE/DIAPH1 Pathway

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

  • ACS Chem Neurosci. 2021 Jan 6;12(1):63-78. doi: 10.1021/acschemneuro.0c00530.
Lingling Shen 1 2 Tianyuan Zhang 1 2 Yu Yang 1 2 Dan Lu 1 2 Anding Xu 1 2 Keshen Li 2


  • 1 Department of Neurology and Stroke Centre, the Fist Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 2 Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, China.

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


Receptor for advanced glycation end-product antagonist; S100 calcium-binding protein B; advanced glycation end products; amyloid-β; distal middle cerebral artery occlusion; rat stroke model.