Effects of pharmacological inhibition of glutamate-uptake on ischaemia-induced glutamate efflux and anoxic depolarization latency.
It has been proposed that deficient glutamate uptake, by increasing the extracellular concentration of this excitatory neurotransmitter, may contribute to the pathophysiology of cerebral ischaemia. This study aimed to examine whether pharmacological inhibition of glutamate uptake altered the kinetics of ischaemia-induced glutamate efflux, and precipitated anoxic depolarisation. Microdialysis was used for application of the glutamate-uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC), recording of the EEG and extracellular direct current (DC) potential with an electrode within the probe, and continuous monitoring of changes in extracellular glutamate. L-trans-PDC was applied locally from 8 min prior to cardiac arrest to the end of the recording period. L-trans-PDC (2.5 mM) barely altered the time course of postmortem glutamate efflux in the cortex. Only the maximum rate of efflux during the first exocytotic phase, and the concentration reached at the end of this phase, appeared slightly increased. L-trans-PDC (5 mM) reduced significantly the delay between EEG silence and anoxic depolarization in the cerebral cortex (59.2 +/- 9.2 s vs. 79.7 +/- 11.5 s; n = 6), but not in the striatum and hippocampus. These effects contrast with the marked increase in dialysate glutamate that L-trans-PDC produces in all these three brain regions. Together, these data do not support the hypothesis that inhibition of glutamate uptake plays a critical role, early in cerebral ischaemia. However, a contribution of reversed glutamate uptake to the secondary Ca2+-independent phase of ischaemia-induced glutamate efflux cannot be ruled out.
Obrenovitch
T P
TP
Gough-Cooper Department of Neurological Surgery, Institute of Neurology, London, UK.
Zilkha
E
E
Urenjak
J
J
D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D017551:Microdialysis; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*
D003998:Dicarboxylic Acids; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid