Valproate doubles the anoxic survival time of normal developing mice: possible relevance to valproate-induced decreases in cerebral levels of glutamate and aspartate, and increases in taurine.
We have previously reported that chronic administration of valproate in developing mice decreased brain aspartic and glutamic acid levels and increased the brain taurine content. The direction of the valproate-induced changes in the cerebral levels of these neurotransmitter amino acids - excitatory in the case of aspartate and glutamate, inhibitory in the case of taurine - appeared relevant to the mechanism of its anticonvulsant action. Since the neuropathology of hypoxia-ischemia also appears to be mediated by release of glutamate/aspartate at the synapse, the valproate-induced reduction of the levels of these neuroexcitatory/neurotoxic amino acids suggested that valproate might increase the tolerance of young mice to anoxia. A doubling of the length of survival of the intact animal in an atmosphere of pure nitrogen gas and a three-fold increase in the duration of respiratory activity (gasping) of the isolated head after chronic administration of valproate support the speculation.
Thurston
J H
JH
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, Missouri 63110.
Hauhart
R E
RE
D000818:Animals; D000833:Animals, Suckling; D001224:Aspartic Acid / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D013654:Taurine / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
D005971:Glutamates; D013654:Taurine; D001224:Aspartic Acid; D014635:Valproic Acid; D005947:Glucose