Neuroprotective Effects And Mechanisms Of Sevoflurane Preconditioning By Attenuating Blood-brain-barrier Leakage After Focal Cerebral Ischemia And Reperfusion In Adult Rats

Recent epidemiological investigations have determined that some neurosurgical, vascular, and cardiovascular procedures, such as carotid endarterectomy, intracranial aneurysmectomy and aorta arteriorrhaphy in deep hypothermia, present a high risk for transient cerebral ischemia and reperfusion (I/R). Perioperational cerebral I/R may induce permanent neurologic deficits in patients. Despite of extensive researches on I/R, no effective strategy is clinically available for the prevention and treatment of this injury. Inhalational anesthetics have been reported to effectively precondition the brain against experimental ischemic injuries in vivo and in vitro. The molecular and cellular mechanisms have been implicated to include electrophysiological and metabolic modulation, reduction of glutamate-mediated excitotoxicity, antioxidant and anti-apoptosis mechanisms. However, impact on blood-brain-barrier (BBB) function by inhalational anesthetics pretreatment in stroke remains unknown. During I/R, upregulated cell adhesion molecules (CAMs) and matrix metalloproteinases (MMPs) have been known to mediate the firm adhesion of leukocytes to sites of inflammation and degrading neurovascular matrix, such as base membrane and tight-junctions (TJs). We therefore assessed the hypothesis that sevoflurane preconditioning provided neuroprotection by attenuation of BBB leakage via suppression of CAMs and MMPs against transient focal cerebral ischemia in rats.Transient focal cerebral I/R was induced by using 60 min of middle cerebral artery occlusion (MCAO) in adult male Sprague-Dawley rats. The animals were exposed for 30min per day on 4 consecutive days to ambient air (sham and vehicle group) or to 1.2%sevoflurane (sevo-pre group), and then subjected to MCAO 24 hours later. BBB integrity was detected by transmission electron microscopy and evans blue (EB) extravasation measurements at 2 days after ischemia. The activation of astrocytes and microglia cells and expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and occludin was also measured by using western blotting, gelatin zymography and immunofluorescence at 6 hours to 3 days after ischemia.In our study, sevoflurane pretreatment markedly alleviated ischemia-induced neurologic deficits. Electron microscopy and EB extravasation measurements showed that the BBB of stroke rats in vehicle group were severely disrupted during I/R, compared with those in sevo-pre group. Ischemia-induced increases in ICAM-1, VCAM-1, MMP-2, MMP-9 and TIMP-1 and decreases in occludin were significantly inhibited in sevo-pre group, but not in vehicle group. Sevoflurane pretreatment suppressed the activation of astrocytes and microglia cells in ipsilateral cortex, striatum and corpus callosum.In conclusion, repeated preconditioning with sevoflurane confered potent neuroprotection against ischemic brain injury partly by improving BBB integrity via suppressing leukocytes adhesion mediated by CAMs, degrading neurovascular TJs mediated by MMPs, and suppressing the activation of astrocytes and microglia cells. Thus, sevoflurane pretreatment is a potential therapy for ischemic brain injury.