Protection of cerebral microvasculature after moderate hypothermia following experimental focal cerebral ischemia in mice

Abstract

Clinical studies have shown that the treatment of ischemic stroke with hypothermia is promising. In this animal study, we investigated the fate of the microvasculature following focal cerebral ischemia in mice with and without hypothermia. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCAO) (3 h) with an intraluminal filament technique. Eight mice received normothermia (36.5 °C, NT) and eight received hypothermia (32–34 °C, HT) treatment during 24 h of reperfusion. Another six mice represented the sham group. Analysis of the hypothermic group in comparison to the normothermic group revealed a significantly reduced infarct volume (NT: 63.56 ± 4.62 mm 3 SEM, HT: 38.09 ± 4.83 mm 3 SEM; P < 0.01) and showed considerably ameliorated neurological deficits (Garcia-score) after 24 h ( P < 0.01). In addition, the degradation of the microvascular basal lamina antigen collagen type IV after normothermia was strongly reduced ( P < 0.05) compared to sham. Hypothermia diminished this effect so that collagen type IV was not significantly reduced compared to sham. Moreover the hemoglobin extravasation was strongly reduced under hypothermic treatment compared to the normothermic group ( P < 0.01). In the hypothermia group the urokinase plasminogen-activator (uPA) activity ( P = 0.01) was significantly decreased compared to the normothermia group. Also MMP-9 was significantly reduced ( P < 0.05) during hypothermic treatment. In conclusion, for the first time we show in mice that hypothermia preserves the microvascular wall structures after ischemia. We have demonstrated that hypothermia protects the basal lamina, reduces the infarct volume and hemorrhage, and reduces proteolytic enzymes. These protective effects in an additional animal model of ischemia and reperfusion strongly recommend hypothermia as a potential beneficial treatment for stroke.