Effect of Delayed Mild Brain Hypothermia on Edema Formation After Intracerebral Hemorrhage in Rats

Secondary consequences of intracerebral hemorrhage (ICH) including inflammation, edema, and oxidative damage all contribute to cell death after ICH. Brain hypothermia (BH) has been used as an effective neuroprotective treatment in experimental brain ischemia and traumatic brain injury. In this study, we first attempted to evaluate the effect of delayed mild BH (35°C) on brain edema formation 48 hours after ICH. BH was started 3, 6, 12, and 24 hours after the induction of 100 μL of autologous blood into the basal ganglia (hypothermic [HT]; HT3: n = 4, HT6: n = 6, HT12: n = 11, HT24: n = 6) in rats. To examine the protective mechanism of BH, blood-brain barrier (BBB) permeability to Evans blue, accumulation of polymorphonuclear leukocyte, and oxidative DNA damage in the lesion were compared between normothermic (NT) (37°C) and HT6 rats 48 hours after ICH. Finally, neurologic recovery was assessed using behavioral tests in NT and HT6 rats 48 hours after ICH. Brain water content in the ispilateral basal ganglia was significantly reduced with delayed BT compared with NT (n = 7, 81.8 ± 0.7% v HT3: 78.9 ± 0.8%, P < .01; HT6: 78.7 ± 0.6%, P < .01; HT12: 79.4 ± 1.1%, P < .01; HT24: 80.3 ± 0.6%, P < .01). The BBB disruption to Evans blue was significantly reduced with BH (HT6: n = 6) compared with NT (n = 6) rats in the ipsilateral basal ganglia (23.0 ± 5.2 v 42.3 ± 4.0 ng/g wet tissue, P < .05). HT6 treatment (n = 6) significantly inhibited the accumulation of polymorphonuclear leukocyte compared with NT treatment (n = 6) (0.43 ± 0.22 v 1.49 ± 0.61 ΔAbs/mg tissue, P < .05). HT6 treatment (n = 3) also significantly reduced oxidative DNA damage determined with 8-hydroxyl-2'-deoxyguanosine compared with NT treatment (n = 3) (92 ± 18 v 40 ± 7 pg 8-hydroxyl-2'-deoxyguanosine/μg DNA, P < .05). Furthermore, HT6 treatment (n = 5) significantly improved neurologic recovery assessed with forelimb placing score compared with NT treatment (42.0 ± 5.8 v 12.0 ± 3.7, P < .05). In conclusion, mild BH significantly reduces the brain edema formation after ICH, even when the BH is applied 24 hours after hematoma induction in rats. Several neuroprotective mechanisms, including reduced BBB disruption, inflammation and oxidative damage, are suggested in this study.