The Role And Mechanism Of Miconazole In The Myelin Regeneration After Subarachnoid Hemorrhage

Background:White matter injury(WMI)after subarachnoid hemorrhage(SAH)has dual characteristics similar to traumatic brain injury and cerebral ischemia.White matter myelin injury after SAH often leads to cognitive neurological dysfunction,while the pathological mechanisms of which have not been fully revealed.Promoting the proliferation and differentiation of oligodendrocyte progenitor cells(OPCs)into mature myelinated oligodendrocytes(mOL)in demyelinating diseases such as multiple sclerosis can achieve myelin regeneration and repair.It has been found that miconazole has the potential to promote myelin growth and is associated with the mitogen-activated protein kinase(MAPK)signaling pathway.However,whether miconazole can promote OPC differentiation and myelin regeneration via MAPK signaling pathway after SAH has not been revealed.Methods:1.Before and after the intervention of miconazole for SAH,the extent and degree of myelin damage was detected by immunofluorescence(IF)and electron microscopy(TEM),the expression of myelin-related proteins MBP and MOG was detected by WB,and the change of OPC/mOL by cell count,while the modified Garcia score,balance beam test were used to assess the alteration of neurological function in SAH rats.The blood-brain barrier disruption was assessed by brain water content.2.After silencing Ras protein with Ras adenovirus and Raf/MEK/ERK signaling pathway inhibitors,the expression of myelin-related proteins MBP,MOG and pathway proteins were detected by WB to reveal the mechanism of miconazole in repairing post-SAH myelin damage.Results:1.White matter myelin damage existed after SAH,peaked at 72h,and leveling off at 7d.The amount of mOL increased slightly at 24h after SAH,then decreased to the minimum at 72h(p<0.01),then increased slowly and returned to the original baseline level about 7d.2.White matter myelin damage was significantly reduced after SAH after miconazole intervention(p<0.05),and the number of OPC/mOL was significantly increased(p<0.05),while significantly improving the neurobehavioral performance of rats after SAH(p<0.05),and reducing cerebral edema.In addition,the miconazole 40mg/kg obtained a better therapeutic effect than 10mg/kg.3.Compared with the control group,knockdown of Ras inhibited myelin regeneration,while overexpression of Ras promoted myelin regeneration.Myelin regeneration was increased after inhibition of Raf and MAPK,and was also inhibited after inhibition of ERK.Conclusions:1.Acute white matter myelin injury progresses and worsens after SAH,with limited OPC proliferation and differentiation and insufficient myelin regeneration.2.Miconazole significantly promotes OPC proliferation and differentiation as well as myelin regeneration and repair after SAH,and improves nerve function after SAH.3.Ras/Raf/MEK/ERK pathway is involved in regulating the process of myelin regeneration and repair after miconazole promoting SAH.