Mechanism Of Intracarotid Lidocaine In Improving Cerebral Ischemiareperfusion Injury

BACKGROUND Stroke is one of the critical illnesses in central nervous system,ranking second among the leading causes of death in the world.Ischemia stroke is the most common form.Vascular recanalization is the main way to treat ischemia stroke,but a large amount of blood inflow during reperfusion leads to cerebral ischemiareperfusion injury.At present,various preventions for cerebral ischemia-reperfusion injury,such as drugs,low temperature treatment,etc.,have their own advantages and disadvantages.As one of the neuroprotection agents,lidocaine is believed to be associated with neuronal function improvement,inflammation inhibition and other effects.However,the adminstration of lidocaine has not been standardized,and the specific mechanism is still unknown.In previous studies,systemic administration of lidocaine was often used,with long administration time and large dose,while the clinical effect was unstable.Intracarotid administration may be an ideal alternative way because of its rapid effect on the brain with a small amount of dosage.Current research on the mechanism of cerebral ischemia-reperfusion injury often focuses on microglia,whose activation can mediate the infiltration of circulating immune cells through the release of chemokines.Both microglia and circulating immune cells induce inflammatory responses.If intracarotid lidocaine is used,will it present neuroprotection by acting on microglia?In addition,lidocaine can affect peripheral and central vasomotor.If intracarotid lidocaine is used,will it affect cerebral blood flow after reperfusion?Both questions are yet to be explored.METHOD Transient middle cerebral artery occlusion model of C57BL/6 was established.Lidocaine was continuously infused through tail vein 30 min before surgery(2 mg/kg bolus followed by 2 mg/kg/h until the onset of ischmia)or injected through internal carotid artery(0.5 mg/kg)at the onset of reperfusion,and the behavioral changes and the cerebral infarct after 24 h of cerebral ischemia-reperfusion injury were compared.The effect of lidocaine on the activation and polarization of microglia,and the survival of BV2 microglia after oxygen-glucose deprivation/reoxygenation in vitro were examined.Using laser speckle contrast imaging,the change of static blood flow in the middle cerebral artery and acetazolamide-induced hyperperfusion within 24 h of reperfusion were also examined.RESULT There was no significant difference in neurobehavioral and cerebral infarct volume in tMCAO mice treated with continuous lidocaine infusion through tail vein at 24 h compared with vehicle group.When appling intracarotid lidocaine,the size of infarct was reduced significantly with improved behavioral test compared with vehicle group.It was found that lidocaine had no significant effect on the activation and polarization of microglia in vivo.Lidocaine also had no protective effect on BV2 microglia after oxygen-glucose deprivation/reoxygenation in vitro.The result of cerebral perfusion demonstrated that lidocaine could significantly inhibit the increased blood flow of middle cerebral artery under hyperperfusion in the brain,though the static blood flow did not change.There was no significant change in the level of cerebral endothelial nitric oxide synthase(eNOS)during hyperperfusion after lidocaine application.CONCLUSION Administration of lidocaine via the internal carotid artery was superior to intravenous administration and presented a more stable neuroprotection from cerebral ischemia-reperfusion injury,which is related to the inhibition of hyperperfusion during reperfusion rather than the regulation on microglia,and the relation to eNOS was not found.