Mitochondrial function and energy metabolism after hypoxia-ischemia in the immature rat brain: involvement of NMDA-receptors.
Treatment after hypoxia-ischemia (HI) in immature rats with the N-methyl-D-aspartate receptor (NMDAR) antagonist dizocilpine maleate (MK-801) reduces areas with high glucose utilization and reduces brain damage. The object was to study the metabolic effects of MK-801 treatment after HI. Seven-day-old rats were randomized to the following groups: non-HI, HI, or HI plus MK-801 (0.5 mg/kg immediately after HI). In the parietal cortex, the mitochondrial respiration was measured in homogenates 1 to 4 hours, and the energy metabolites at 3 and 8 hours after HI. The energy use was calculated from changes in energy metabolites after decapitation at 3 hours after HI. State 3 respiration was reduced by 46%, 32%, and 25% after HI compared with non-HI with pyruvate plus malate, glutamate plus malate, or glutamate plus succinate as substrates, respectively. Uncoupler-stimulated but not state 4 respiration was similarly reduced. The MK-801 augmented pyruvate plus malate-supported state 3 respiration after HI by 42%. The energy utilization was not affected by HI but was reduced by MK-801 treatment in the ipsilateral cortex from 4.6 +/- 2.3 to 2.6 +/- 1.8 micromol high-energy phosphate bond/min/g. The levels of ATP and phosphocreatine did not differ between the HI and HI plus MK-801 groups at 3 hours, but were lower in the HI than in the HI plus MK-801 group at 8 hours after HI. In conclusion, treatment with MK-801 reduced energy utilization and improved mitochondrial function and energy status after HI, suggesting a linkage between NMDAR activation and impaired energy metabolism during reperfusion.
Gilland
E
E
Department of Obstetrics and Gynecology, Göteberg University, Sweden.
Puka-Sundvall
M
M
Hillered
L
L
Hagberg
H
H
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate