The Therapeutical Effect Of RAGE Specific Antagonist FPS-ZM1 In Focal Cerebral Ischemia Rats

Background: The receptor for advanced glycation end-products(RAGE)is a multi-ligands receptor,belonging to the cell surface immunoglobulin superfamily.It was extensively reported that RAGE played a crucial role in neuroinflammatory and neurodegeneration diseases.In this study,we further investigated the pathophysiological effect of RAGE and the therapeuticaleffect of its specific antagonist FPS-ZM1 in focal cerebral ischemia rats to provide an experimental evidencefor the future clinical translational research.Materials and Methods: Firstly,46Sprague-Dawley male rats were anesthetized and received either permanent middle cerebral artery occlusion(pMCAO)or Sham operation.Then the neurological deficit,the expression levels of RAGE,advanced glycation end-products(AGE)and High mobility group box 1(HMGB1),the number of S100 calcium-binding protein B(S100B)positive cells in cortex were respectively assessedat12 h,1 day,3 days,7 days,14 days and 30 days after the operation.In the second part,18 Sprague-Dawley male rats were randomly grouped to intraperitoneally inject FPS-ZM1 in different concentrations consistentlyfor 7 days after pMCAO surgery and subsequently detected the RAGE expression in contex.Thirdly,61Sprague-Dawley male rats were intraperitoneally injected 1 mg/kg FPS-ZM1 for 7 days after pMCAO,following neurological deficit,2,3,5-triphenyltetrazolium chloride(TTC)staining,Nissl staining,the detection of nuclear factor kappa-B(NF-?B)pathwayprotein and pro-inflammatorycytokines.Results: The expression of RAGE and AGE in the ischemic core and the periphery and the number of S100 B positive cells in the periphery gradually increased afer pMCAO and reached to the peak at day7 in focal cerebral ischemia rats.Treatment with FPS-ZM1,a RAGE specific antagonist,significantly attenuated the neurological deficit,decreased infarct areas and necrotic neurons in ischemic periphery,suppressed the expression of RAGE,AGE and S100 B,inhibited the activation of NF-?B pathway and pro-inflammatorycytokines in infarcted ipsilateral core and periphery and reduced the A? depositon in the ischemic core and the periphery.Conclusion: The ascended expresstion of RAGE and its ligands AGE and S100 B is associated with neurological deficit in focal ischemia rats in short term.RAGE specific antagonistFPS-ZM1 is of potential therapeutical effect in cerebral infarction treatment,as it blocks RAGE/NF-?B pathway,reduces the expression of RAGE,S100 B and pro-inflammation cytokines,lessens the accumulation of AGE and A?,decreases the infarct areas and dead neuronsand attenuates the neurological deficit in focal cerebral ischemia rats.