Ethanol Asmetabolic Precursor and Fuel for the Brain

Background: Previous studies in humans and rats have shown ethanol (Etoh) consumption to decrease brain glucose utilization, and ethanol, which is converted to acetate (Ac), increases brain Ac uptake. We have seen that in humans, Ac transport and oxidation are faster in heavy drinkers than light drinkers. It is unknown if Ac only or if Etoh also provides energy to the brain. Methods: Rats were treated 3 weeks with ~23 mg/L Etoh vapor (treated), or room air (na€ıve), for 8 hr/day. In Study 1, na€ıve and treated rats (n = 9 and 8) were fasted and given [2-C]Etoh (EtohC2) via a tail vein to maintain blood Etoh at 25 mM for two hours. The brain was fixed by focused microwave and the cortex extracted for MRS analysis of glutamate (Glu) and glutamine (Gln) C labeling. In Study 2, na€ıve and treated rats (n = 10 and 9) received co-infusions of EtohC2 and [1, 2-C2]Ac (AcC12) to maintain blood EtOH at ~28 mM and Ac at ~3 mM for 2 hours. Then the brain was fixed and the cortex processed for MRS analysis of double-labeled and single-labeled Glu and Gln. Etoh oxidation is present if the ratios of GluC4/GluC45 and GlnC4/GlnC45 are greater than AcC2/AcC12. Results: In Study 1, rats given EtohC2 elevated blood AcC2. Vapor-treated rats consumed more C (p < 0.01). Based on previous findings in humans and rats, much of that came from Ac, but EtOHmight contribute. In Study 2, both groups had significantly more GlnC4/GlnC45 andGluC4/ Glu45 than AcC2/AcC12 (p < 0.001), proving intracerebral Etoh oxidation. In na€ıve rats Etoh provided 6.8 0.8% and 3.4 0.4% of glial and neuronal oxidation, respectively, and for treated rats the figures were 11.0 0.8% (p = 0.0015 increase with treatment) and 3.3 0.1%. Discussion: Given the cerebral energy budget, Ac and ketone bodies elevated by Etoh could provide 8–12% of brain energy. Another 1–2% comes from intracerebral oxidation of ethanol, would correspond to reductions of glucose uptake reported for humans consuming alcohol. From Group 2, using published glial and neuronal Krebs cycle rates, we estimate brain Etoh oxidation at ~0.03 mmol/min/g. Oxidation of EtOH generates acetaldehyde, which in the brain is rewarding, but it also creates oxidative stress and might be pro-inflammatory in the brain. Oxidation of acetate, which is faster than Etoh oxidation in the brain, is inflammatory in the liver andmay also be inflammatory in the brain. Etoh can provide energy for the brain, directly and via Ac, but the oxidation may theoretically be damaging.