Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia.
Studies over the past decade have demonstrated that lactate is produced aerobically during brain activation and it has been suggested to be an obligatory aerobic energy substrate postischemia. It has been also hypothesized, based on in vitro studies, that lactate, produced by glia in large amounts during activation and/or ischemia/hypoxia, is transported via specific glial and neuronal monocarboxylate transporters into neurons for aerobic utilization. To test the role of lactate as an aerobic energy substrate postischemia in vivo, we employed the cardiac-arrest-induced transient global cerebral ischemia (TGI) rat model and the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxycinnamate (4-CIN). Once 4-CIN was establish to cross the blood--brain barrier, rats were treated with the inhibitor 60 min prior to a 5-min TGI. These rats exhibited a significantly greater degree of delayed neuronal damage in the hippocampus than control, untreated rats, as measured 7 days post-TGI. We concluded that intra-ischemically-accumulated lactate is utilized aerobically as the main energy substrate immediately postischemia. Blockade of lactate transport into neurons prevents its utilization and, consequently, exacerbates delayed ischemic neuronal damage.
Department of Anesthesiology, University of Louisville School of Medicine, Louisville, KY 40292, USA. a0schu01@gwise.louisville.edu
A
A
Schurr
R S
RS
Payne
J J
JJ
Miller
M T
MT
Tseng
B M
BM
Rigor
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism*; D003373:Coumaric Acids / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D027501:Monocarboxylic Acid Transporters; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D003373:Coumaric Acids; D027501:Monocarboxylic Acid Transporters; C091633:Slc16a7 protein, rat; C007175:alpha-cyano-4-hydroxycinnamate; D019344:Lactic Acid