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Abstract: The rewarming phase after therapeutic hypothermia in cerebral ischemia appears crucial as rapid rewarming may lead to rebound phenomena and enhance deleterious ischemic effects. We hypothesized that slow and controlled rewarming after moderate hypothermia is superior to fast rewarming in rats subjected to 90 min temporary middle cerebral artery occlusion (tMCAO). Two experiments were designed: (i) 34 rats were randomly assigned to either normothermic treatment, to hypothermia (33°C) with rapid rewarming within 20 min, or to hypothermia with slow rewarming within 2 h after 4 h of hypothermia starting 2 h after tMCAO. Infarct size, neuroscore, myeloperoxidase and aquaporin 4 (AQP4) positive cells were assessed on day 5 after tMCAO. (ii) In 15 rats, striatal cerebral microdialysis was performed from 1.5 h before until 8 h after tMCAO. Total infarct volume was largest in the normothermic group (89.9±16.8 mm3) followed by the fast rewarming group (69.2±12.6 mm3), and a significantly smaller infarct volume in the slow rewarming group (41.1±6.6 mm3, p <0.05). Neurological functions improved in both hypothermia groups at day 5 after tMCAO (Neuroscore median 2.5 in normothermia vs. 1.5 in both hypothermia groups) though without any difference between slowly and fast rewarmed animals. Periinfarct expression of AQP4 was less prominent in slowly rewarmed animals as was the count of MPO-positive cells in subcortical regions. Glutamate release was significantly higher at 4 distinct time points in the control group. Slow rewarming after a period of hypothermia is superior to fast rewarming. It may blunt deleterious rebound effects such as overexpression of AQP4, sustain anti-inflammatory mechanisms and thereby preserve the neuroprotection delivered by hypothermia. [Copyright &y& Elsevier]