Cerebral Lactate And Monocarboxylate Transporters Are Reduced By Ethanol And Normobaric Oxygen Therapy After Severe Transient And Permanent Ischemic Stroke

Objectives: Recent studies conducted by this lab have shown the neuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO), which is partially due to amelioration of aberrant glucose metabolism and a reduction in reactive oxygen species (ROS). In the current study, we sought to identify whether the neuroprotective benefits of EtOH, with or without NBO, attenuates lactic acidosis by reducing expression of monocarboxylate transporters (MCTs), resulting in ROS reduction after transient and permanent ischemic stroke. Methods: Sprague-Dawley rats (n=64) were subjected to right middle cerebral artery occlusion (MCAO) for 2 h or 4 h (transient ischemia), or 28h (permanent ischemia) followed by 3h, 24h, or no reperfusion. Rats in each group were randomly assigned to receive either an injection of saline (sham treatment), an intraperitoneal injection of EtOH (1.5g/kg), two doses of EtOH (1.5g/kg at onset of reperfusion followed by 1.0 g/kg 2 h after 1 st dose), or EtOH + 95% NBO for 6 h (permanent ischemia). Lactate and ROS levels were detected at 3h and 24h following reperfusion. Gene and protein expressions of MCT-1, MCT-2, and MCT-4 were assessed by RT-PCR and Western Blotting, respectively. Results: A dose dependent neuroprotection of EtOH administration was found in transient ischemia. Single dose in 2 h MCAO and double dose in 4 h MCAO significantly attenuated lactate levels and ROS generation, MCT-1, MCT-2, and MCT-4 mRNA and protein expression after severe transient ischemia. However, EtOH treatment alone, even with 2 doses, was insufficient for permanent stroke, while combination therapy (EtOH + 95% NBO) resulted in a more potent decrease of all levels and expressions. Conclusions: Our study suggests that acute EtOH administration can attenuate lactic acidosis-induced oxidative stress following a transient ischemic stroke. This EtOH-induced attenuation of brain injury was enhanced by NBO in permanent ischemic stroke. Both EtOH and NBO are widely available, inexpensive, easy to administer, and have few side effects. Ultimately, this combination therapy could be an effective approach to future stroke treatments.