Significance And Mechanism Of CX3CR1in The Process Of Ischemic White Matter Lesions

White matter lesions (WMLs) induced by chronic cerebral hypoperfusion (CCH) havebeen suggested to contribute to cognition impairment, which causes serious damage to humanhealth. Inflammation, oxidative stress and dysfuction of synatic structure are involved in thepathologic progress. For many years, increasing evidence indicates that inflammation plays acritical role in the pathogenesis of WMLs. In WMLs, microglia plays a dual role in diseaseprogression, being essential for clearing necrotic tissues and releasing of neurotrophic factors.Once the number of actived microglia is high, it can damge the normal tissue by producingsome inflammatory factors. CX3CR1, exclusively expressed by microglia in the brain,contributes to the ability of microglia to maintain a resting phenotype. CX3CR1has an effecton some disorders, such as acute ischemia, degenarative diseases and nerve damages.However, there is no study conferring to CX3CR1involved in the WMLs after CCH.p38MAPK, one of the important members in the MAPK families, is mainly involved ininflammation. It is unclear whether p38MAPK is involved in the process of WMLs inducedby CX3CR1after CCH.Objective: The purpose of our study was to examine the relationship of CX3CR1withWMLs in CCH; to further study p38MAPK in the pathogenesis of CX3CR1invovled inWMLs. Methods: CCH was induced by permanent occlusion of bilateral common carotidarteries (BCCA) in male Wistar rats.320rats were randomly divided into five groups asfollows:(i)normal;(ii)sham-operation group;(iii)rats exposed to BCCA contribute to CCH;(iv)rats received control anti-IgG antibody or DMSO then exposed to BCCA;(v) rats receivedlateral ventricle stereotaxic injection of anti-CX3CR1neutralizing antibody or a p38inhibitorthen exposed to BCCA. Performance of Morris water maze task and the relationship ofCX3CR1with CD11b are analyzed at28d after CCH. Hematein Eosin(HE) and Luxol FastBlue(LFB) for white matters(corpus callosum, internal capsule and optic nerve), Western Blotfor CX3CR1and p38MAPK, immunohistochemistry for the progress of microglia areanalyzed at different times(1d,3d,7d,14d,28d) after post-hypoperfusion. All of above objectives were measured after post-hypoperfusion with lateral intraventricular injection ofdifferent concentration CX3CR1neutralizing antibodies or a p38inhibitor. Results：(1) Onthe28thafter surgery, compared with the control group, BCCA group significantly increasedthe mean escape latency, path length and reduced the numbers that the rats crossed over theposition where the platform located(P<0.01).(2) HE staining showed fibers lossen,disorganization and vacuolus in the corpus callosum, internal capsule and optic nerve. LFBstaining showed that increased number of vacuoles and demyelinated fibers in the abovewhite matters. A gradual increase in CX3CR1protein levels was observed in white mattersand CD11b marked activated microglia was almost at similar levels in these areas(P<0.01).(3)The ratio of P-p38/p38in white matters was significantly higher at the3rdafterpost-hypoperfusion, which had relationship with the alternation of CX3CR1.(4)Theadministration of anti-CX3CR1neutralizing antibodies, in which therer is an optismconcentrtion, alleviated behavior, white matters, microglia activation and the alternation ofP-p38/p38in rats with CCH. The administration of a p38inhibitor alleviated white mattersand microglia activation. Conclusion：(1) CX3CR1over expression has a bad effect byaffecting microglia on white matters after CCH, which plays an important role in learning andmemory.(2) CX3CR1/p38MAPK signaling is one of the pathogenesis in the WMLs afterCCH.