尚无神经保护剂被循证医学证明有效，低温是唯一在临床证明有效的脑保护措施，但仅限于缺血缺氧性脑病。我们以冰盐水颈内动脉灌注证实选择性脑低温能缩小MCAO大鼠的梗塞面积，并减少全身低温的副作用，但维持脑低温需要大量的液体。进一步研究表明，间断多次冰盐水颈内动脉灌注同样有脑保护作用，并可将冰盐水的灌注量减少至1/3左右，以硫酸镁替换生理盐水加强了脑保护效果，且有协同作用。研究证实动脉内置管7天无副作用，我们设想利用颈内动脉置管可以将选择性脑低温和局部动脉给药联合起来，并相互增强作用。本项目拟在体外缺血性卒中细胞模型上研究间断多次低温的神经保护作用，筛选与低温有协同作用的药物，研究协同作用的环节。进一步在大鼠MCAO模型上研究颈内动脉给药的优势，与间断多次选择性脑低温的协同作用和机理。旨在获得间断低温联合神经保护剂的有效证据和可行方案，为选择性脑低温联合颈内动脉给药治疗重症缺血性卒中提供实验依据。

All neuroprotectants are failure to clinical translation. Hypothermia is the only effective neuroprotective therapy proved by clinical trials but limitted to hypoxic-ischemic encephalopathy (HIE). Intracarotid cold saline infusion (ICSI) shows that selective brain cooling (SBC) can significantly reduce the cerebral infarction area in middle cerebral artery occlusion (MCAO) rats and minimize the side effects of systemic hypothermia in our preliminary study. Nevertheless, at least 10000 ml cold saline should be infused to maintain SBC for 24 hours in human by caculation. Our further study indicate that intermittent multiple ICSI is not only neuroprotective but also reduces the volume of cold saline to 1/3 at least. Replacing normal saline by magnesium sulfate shows synergic effect in neuroprotection. With the development of neurointervention and it is possible to place intra-arterial catheter more than 7 days without any side effcts, we propose that the combination of SBC and intracarotid delivery of neuroprotectants may be synergetic effect in neuroprotection, has the potential to be developed into an effective approach for severe ischemic stroke in the future. Thus in this proposal we will further obtain the evidences of neuroprotection of intermittent multiple hypothermia, screen the neuroprotectants which have the synergic effects with hypothermia and clarify the mechanisms of synergic effects in vitro model of ischemic stroke. Further more,we will compare the neuroprotective effects between intracarotid and intravenous delivery of neuroprotectants at the same drug dose, evaluate the mechanism of synergic effect and outcome of combination of intermittent multiple seletive brain cooling and intracarot delivery of neuroprotectants by cellular,histological,pathological,electrophysiological and behavioral analysis using tMCAO rat model in order to promote this new approach to be used in clinic as soon as possible.