Intraischemic mild hypothermia has been shown to be neuroprotective in transient focal ischemia. As a more clinical relevant issue, the effect of postischemic hypothermia on cerebral infarction in a rat model of reversible focal ischemia was investigated. Rats were subjected to 2 hours of middle cerebral artery (MCA) occlusion followed by 22 hours of reperfusion under the following protocols : (1) rats were treated with normothermia (37.0°C, 4 hours) and then housed in a room maintained at 25°C for 18 hours; and (2) rats were treated with hypothermia (33°C, 4hours) and then housed in a cold room maintained at 5°C for 18 hours. After 24 hours of the MCA occlusion, a significant reduction in volume of infarction was found in the postischemic hypothermia group compared to the normothermic group. Postischemic hypothermia also significantly reduced the accumulation of poymorphonuclear leukocytes (PMNLs) and suppressed the overexpression of intercellular adhesion molecule-1 (ICAM-1) mRNA. In conclusion, ischemic brain damage can be reduced by a mild and prolonged postischemic hypothermia in a focal model of transient cerebral ischemia. The neuroprotective mechanism of postischemic hypothermia may be mediated by suppression of leukocytemediated inflammation after ischemia and reperfusion.
Hypothermia has a neuroprotective effect for ischemia. The aim of this study was, therefore, to determine whether mild hypothermia (35°C) would enhance neuroprotecive effects of immunosuppressant FK 506 for focal ischemia. The left MCAO were occluded for 2 h by intraluminal suture and reperfused for 24 h. Animals were randomly devided into the following four groups. (I) vehicle-treated, normothermic (37°C) group (II) vehicle-treated, mild hypothermic (35°C) group (III) FK 506-treated, normothermic (37°C) group (IV) FK 506-treated, mild hypothermic (35°C) group. FK 506-treated animals received a single injection of FK 506 (0.3 mg/kg) intravenously 120 min after the onset of ischemia, while vehicle-treated groups received same dose of vehicle. The cortical and striatal infarct volume in group IV was significantly reduced compared with that in group I (p<0.001), whereas there was no significant difference between group II or III and group I. Moreover, edema volume in group IV was significantly smaller than that in group I (p<0.05). These results demonstrate that a combined therapy with mild hypothermia (35°C) and FK 506, each has no neuroprotective effects alone, significantly reduces the ischemic brain damage and enhances neuroprotecive actions for focal ischemia in rats.
超急性期の重症心原性脳塞栓症患者13例(年齢59±11歳,男9例)に軽微低体温療法を施行した.閉塞血管は内頸動脈7例,中大脳動脈5例,脳底動脈1例で,入院時のNIH Stroke Scaleは12～37(中央値25)であった.低体温は,発症後6時聞以内に導入し,3～7日間脳温33℃に維持した.2例が急性期に死亡,1例は早期に開頭術施行となった.開頭例を除く12例の90日後の転帰は,modified Rankin Scale 2以下の良好例が4例(33%),Barthel Index 75以上の良好例は6例(50%)であった.CT所見の特徴は,出血性変化や造影効果が少なく,脳浮腫像も軽微であった.3例では梗塞巣が徐々に拡大し発症後3～7日で梗塞巣が完成し,いずれも閉塞血管が再開通していない例であった.軽微低体温療法は,心原性脳塞栓症発症後の超急性期に導入すれば,神経細胞と血液脳関門を保護することにより効果を発揮するものと考えられ,さらに脳梗塞のtherapeutic time windowを拡大する可能性が示唆された.
Intraoperative mild hypothermia has been used during cerebral aneurysm surgery to reduce ischemic injury induced by temporary vessel occlusion and brain retraction. This study investigated the effect of intraoperative mild hypothermia on cerebral blood flow (CBF) after surgery for aneurysmal subarachnoid hemorrhage (SAH). Twenty-four patients with ruptured internal carotid or middle cerebral artery aneurysms in preoperative Hunt & Hess grade II or III underwent aneurysm clipping within 72 hours after SAH. During surgery, patients were randomly assigned to either intraoperative mild hypothermia (33°C, n=12) or normothermia (37°C, n=12). Brain SPECT with 99mTc-HMPAO or with 99mTc-ECD was performed on day-4, -7, and -14 after SAH. Regional CBF was determined in the basal ganglia, cingulate, frontal, and frontoparietal cortices using a semi-quantitative method. CBF in the frontal cortex ipsilateral to the aneurysm was significantly higher in the hypothermia than the normothermia group on day-4 (p<0.01), but not day-7 or-14. There was a similar trend in the the ipsilateral frontoparietal cortex, but not significant. There was no difference in regional CBF in the ipsilateral cingulate cortex and basal ganglia, and all contrateral regions during the study period. Intraoperative mild hypothermia may reduce the severity of ischemia induced by intraoperative temporary vessel occlusion and brain retraction, thus ameliorating postoperative CBF impairment.
Gene transfer to cerebral arteries is an appealing strategy to modulate vascular function, and an possible technique for treatment of verebrovascular diseases. We have recently reported that gene transfer of calcitonin gene-related peptide in vivo to rabbits prevented constriction of the basilar artery in vivo after experimental subarachnoid hemorrhage, both when the vius was applied before and after hemorrhage. Here, we demonstrate results of this study, and discuss the possibility of gene therapy for stroke.
Recent studies have shown that release of mitochondrial cytochrome c is a critical step in the apoptosis process. We have reported that cytosolic redistribution of cytochrome c in vivo occurred after transient focal cerebral ischemia (FCI) in rats and preceded the peak of DNA fragmentation. Although the involvement of reactive oxygen species in cytosolic redistribution of cytochrome c in vitro has been suggested, the detailed mechanism by which cytochrome c release is mediated in vivo has not yet been established. In this study we examined the subcellular distribution of the cytochrome c protein in both wild-type mice and heterozygous knock-outs of the Mn-SOD gene (Sod 2 - / +) after permanent FCI, in which apoptosis is assumed to participate. Cytosolic cytochrome c was detected as early as 1 hr after ischemia, and correspondingly, mitochondrial cytochrome c showed a significant reduction 2 hr after ischemia (p < 0.01). Cytosolic accumulation of cytochrome c was significantly higher in Sod 2 - / + mice compared with wild-type animals (p<0.05) . A significant amount of DNA laddering was detected 24 hr after ischemia, and increased in Sod 2 - / + mice. These data suggest that Mn-SOD blocks cytosolic release of cytochrome c and could thereby reduce apoptosis after permanent FCI.
中大脳動脈永久閉塞後に同側の頸部頸動脈を15分間一時遮断するモデルでGFAP欠損マウスはwild type littermatesと比較して48時間後の梗塞巣が有意に大きかった.さらに虚血中の局所脳血流量を経時的にモニターしたところ,GFAP欠損マウスでは局所脳血流量の低下がwild type littermatesと比較して有意に広範囲に及んだ.脳虚血の病態に星細胞とその中間径蛋白が重要な役割を担っていることが明らかとなった.