Effects of mild hypothermia on brain edema and HIF-1α, VEGF expression following intracerebral hemorrhage in rats

Abstract

Objective To investigate the effect of mild therapeutic hypothermia for different lengths of time on cerebral edema and hypoxia-inducible factor 1 α (HIF-1α),vascular endothelial growth factor (VEGF) expressions following intracerebral hemorrhage (ICH) so as to explore possible mechanism for better application of mild hypothermia.Methods ICH models were made in rats by stereotaxically injecting autologous artery blood into right caudate nucleus.Forty male Sprague-Dawley (SD) rats were randomly (random number) divided into 5 groups (n =8 each):sham-operated (sham),normothermic (NT),hypothermic-1 hour (MH1),hypothermic-2 hours (MH2),hypothermic-4 hours (MH3).Normothermic and sham-operated animals were kept at (37.0-± 0.2) ℃ of body temperature.Animals in the hypothermic groups received immediately and rapid cooling after ICH and kept at (33.0 ± 0.5) ℃ of body temperature for 1,2 and 4 hours respectively.Rats were sacrificed at 48 hours after cerebral hemorrhage.Then brain water content and BBB permeability were determined.Quantitative real-time PCR and Western blot were used to analyze the expression of HIF-1α and VEGF.Results The content of brain water,Evans blue concentration in brain,and the mRNA expression and protein levels of HIF-1α and VEGF were noticeably higher in NT group than those in sham group (P ＜0.01).There were statistically significant difference in the expression of HIF-lα mRNA and protein but little difference in other indicators between MH1 group and NT group.Compared with NT group,MH2 group and MH3 group brought about an improvement in BBB permeability and remarkable down-regulation of protein levels and expression of HIF-1 α and VEGF mRNA,whereas there were no statistically significant difference in expression of indicators between the two groups.Conclusions Mild therapeutic hypothermia induced rapidly and immediately after ICH could limit the development of brain edema in rats by down-regulating expression and protein levels of HIF-1 α mRNA,and in turn suppressing the evaluation of VEGF mRNA and protein expression.The brain edema was effectively reduced in animals treated with hypothermia for 2 hours' or 4 hours ' duration with little difference in magnitude of reduction in brain edema between these two modalities of hypothermia. Key words: Cerebral hemorrhage; Cerebral edema; Hypothermia; Hypoxia-inducible factor 1 α ; Vascular endothelial growth factor