Study On Effect Of Mannitol On Cerebral Edema And Glycocalyx In Experimental Ischemic Stroke

BackgroundCerebral edema is an important secondary injury of ischemic stroke,and there is no clinically targeted drug application for it now.For intracranial hypertension caused by cerebral edema,osmotic drugs such as mannitol are commonly used,which needed to be restricted in intact blood vessels to play the role of osmotic dehydration.When being used,the effect of mannitol is weakened after repeated administration,and the rebound effect of intracranial pressure often occurs after drug withdrawal,so the role of mannitol in cerebral ischemic stroke and intracranial hypertension is still controversial.Mannitol may also temporarily increase the plasma osmotic pressure and blood volume to facilitate the secretion of atrial natriuretic peptide（ANP）.Furthermore,it is reported that hypervolemia and ANP can damage the glycocalyx coating on the vascular endothelial cell,a negatively charged gel-like ultrastructure layer rich in polysaccharides.However,the effect of mannitol on glycocalyx remains unclear.ObjectivesThis study intends to investigate the effect of mannitol on cerebral edema after ischemic stroke and whether it sheds the glycocalyx of blood-brain barrierMethodsFocal cerebral ischemia was induced by transient middle cerebral artery occlusion in C57BL/6 mice.Follow-up experiments were mainly divided into two parts:1.20%mannitol（1.5g/kg）was injected through tail vein at 24h after modeling,and the mice were divided into single administration and multiple administration（once every 6h,5 times in total）groups,the vehicle groups（injected equal volume of saline）were set respectively.Then edema formation,the degree of mannitol accumulation in brain tissues and the integrity of blood-brain barrier were evaluated at 6-8h after drug administration.2.Firstly,the shedding components in blood and morphological changes of glycocalyx were detected to explore the effect of mannitol on blood brain barrier glycocalyx and its time variation trend in normal and ischemic stroke mice.Then we tested the plasma ANP concentration and its changing trend after medication to investigate whether mannitol affects glycocalyx through facilitating ANP secretion.Results1.Mannitol aggravated cerebral edema after ischemic stroke in mice（1）Multiple administration of mannitol after ischemic stroke aggravated the cerebral edema in the infarct area,and tended to reduce the water content of normal tissues,which increased the degree of midline shift.（2）Multiple administration of mannitol increased the permeability of the blood-brain barrier after ischemic stroke.（3）At 6-8h after administration,the plasma mannitol was excreted,but there was still accumulation of mannitol in the infarct area.2.Mannitol injured the glycocalyx in mice（1）In normal mice,single administration of mannitol resulted in the degradation and shedding of the blood-brain barrier glycocalyx,which reached the peak at 6h after administration.（2）In mice with cerebral ischemic stroke,multiple administration of mannitol further aggravated the destruction of glycocalyx.（3）The plasma ANP concentration of normal mice reached the peak at 6h after mannitol administration,and the plasma ANP concentration also increased at 6h after mannitol administration in ischemic stroke mice.Conclusions1.Mannitol aggravates cerebral edema in the infarct area after ischemic stroke in mice,which may be due to the accumulation of mannitol in brain tissue,resulting in the reversal of osmotic gradient,and its effect on BBB permeability2.Mannitol disrupts the blood-brain barrier glycocalyx in normal and ischemic stroke mice,possibly acting by temporarily increasing the osmotic pressure and whole blood volume to facilitate ANP secretion.The degradation and shedding of glycocalyx may be one of the reasons why mannitol increases blood-brain barrier permeability and aggravates cerebral edema after ischemic stroke.