Modulation of edema by dizocilpine, kynurenate, and NBQX in respiring brain slices after exposure to glutamate.
Brain edema caused by glutamate excitotoxicity was studied in well oxygenated neonatal cerebrocortical brain slices (350 mu thick). Slices exposed to 60 minutes of 2 mM glutamate, with or without glutamate antagonists (dizocilpine, kynurenate, or NBQX), were allowed to recover for 60 minutes. The protocol was identical to that in noninvasive multinuclear NMR spectroscopy studies (31P/1H/19F) of live slices. Percent water and swelling were determined invasively in isolated slices by wet and dry weight measurements before and after glutamate exposure. Edema was detectable within minutes in all experiments with glutamate exposures, but not in untreated control slices. Dizocilpine, kynurenate, and NBQX differently affected swelling, which correlated with PCr and ATP loss in separate NMR studies. Synaptic glutamate receptor activation appears to initiate events causing both edema and energy failure. Multiple glutamate receptor types seem to be involved. No glutamate antagonist provided greater protection against both edema and energy loss than dizocilpine. Dizocilpine might also block voltage-dependent Na+ channels, and provide protection via mechanisms other than NMDA-receptor dependent channel antagonism.
Anesthesia Department, University of California, San Francisco.
M T
MT
Espanol
Y
Y
Xu
L
L
Litt
L H
LH
Chang
T L
TL
James
P R
PR
Weinstein
P H
PH
Chan
D000818:Animals; D001929:Brain Edema / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D046508:Culture Techniques; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D007736:Kynurenic Acid / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009929:Organ Size / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology
D011810:Quinoxalines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D015222:Sodium Channels; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid