Role of zonula occludens-1 in early brain injury after subarachnoid hemorrhage and regulatory mechanism of c-Jun N-terminal kinase

Abstract

Objective To clarify the role ofzonula occludens-1 （ZO-1） in early brain injury （EBI） after subarachnoid hemorrhage （SAH） and regulatory mechanism of c-Jun N-terminal kinase （JNK）to discuss the molecular mechanism of SAH-induced blood-brain barrier （BBB） dysfunction. Methods Seventy-two male SD rats were randomly assigned to sham-controlled, SAH, SAH＋SP600125 （the inhibitor of JNK） and SAH＋ dimethyl sulfoxide （DMSO） groups. SAH models were induced by injection of autologous blood into the cisterna magna of rats, and they were subsequently sacrificed 24 h later. The brain water content was measured, and BBB disruption was evaluated by Evans blue dye;immunohistochemistry was employed to compare the expressions of ZO-1 and JNK. Results As compared with the sham-controlled group, the SAH group 24 h after the success of model making was detected a significant increase of water content, obviously increased Evans blue dye extravasation,especially in the brain stem and cerebellum （P〈0.05） and both structural damage and neuronal damage were noted; the mean optical density of immunohistochemistry showed a strong increase of JNK expression while a obvious decrease of ZO-1 expression was noted in the SAH group 24 h afar the success of model making （P〈0.05）. Treatment with SP600125 could significantly reduce the water content, decrease the Evans blue dye extravasation, inhibit the JNK expression and increase the ZO-1expression as compared with those in the SAH and SAH＋DMSO groups （P〈0.05）, while no significant difference was noted as compared with those in the sham-controlled group （P〉0.05）. Conclusion SAH activates the phosphorylation of JNK, and represses the transcription and translation of ZO-1,subsequently, opens the tight junction and causes brain edema by redistribution of transmembrane proteins and rearrangement ofcytoskeletal proteins, therefore, EBI appears. However, treatment with SP600125 can reverse the above-mentioned processes and improve the outcome of EBI. Key words: Subarachnoid hemorrhage; Brain injury; Zonula occludens-1; c-Jun N-terminal kinase