BRAIN RESEARCH ELSEVIER Brain Research 699 (1995) 121-124 Short communication A comparison of the effects of a sodium channel blocker and an NMDA antagonist upon extracellular glutamate in rat focal cerebral ischemia Jun Chen a, Steven H. Graham a,b, Roger P. Simon a, * a Department of Neurology, 325 Scaife Hall University of Pittsburgh, Pittsburgh, PA 15261, USA b Neurology Serl,ice (127), Department of VeteransAffairs University Drive, Medical Center, University Drive C, Pittsburgh, PA 15213, USA Accepted 28 June 1995 Abstract Agents such as 619C89 decrease extracellular glutamate concentrations by a primary action at voltage sensitive sodium channels, but NMDA antagonists also have been shown to decrease extracellular glutamate concentration after ischemia. To address the question as to whether 619C89's effect upon extracellular glutamate concentrations is any different than the effect of the NMDA antagonist dextrorphan, 24 rats were given either optimally neuroprotective doses of these drugs or saline prior to middle cerebral artery occlusion. In caudate, the 619C89-treated, but not dextrorphan-treated rats had less microdialysate glutamate than ischemic controls. In cortex, both 619C89- and dextrorphan-treated groups had significantly decreased glutamate compared with ischemic controls. These results support a specific effect of 619C89 upon glutamate release in caudate but not cortex. Keywords: Focal cerebral ischemia; N-Methyl-D-aspartate; Glutamate; Microdialysis; Voltage-dependent sodium channel Increased extracellular concentrations of glutamate is now widely accepted as a major neurotoxin in ischemia and pharmacologic blockade of the post-synaptic N- methyl-o-aspartate (NMDA) receptor or its membrane channel have been shown to be neuroprotective in animals [2,3,16]. However, glutamate antagonists acting at the post-synaptic membrane have considerable toxicity, includ- ing hypotension and psychotomimetic effects in humans, and neurocytologic injury in animals [20,23,25]. For these reasons, alternative strategies to attenuate glutamate toxic- ity have been developed. One such alternative strategy is to inhibit the ischemic release of glutamate by voltage sensitive sodium channel blockade. Agents such as 5-(2,3,5-trichlorophenyl)-2,4-di- amino pyrimidine (1003C87) and 4-amino-2-(4-methyl-1- piperazinyl)-5-(2,3,5-trichlorophenyl) pyrimidine (619C89) act at Type IIa voltage-sensitive Na + channels. They have little effect upon the normal closed sodium channel Abbreviations: NMDA, N-methyl-~aspartate; MCA, middle cerebral artery; 1003C87, 5-(2,3,5-trichlorophenyl)-2,4-diamino pyrimidine; 619C89, 4-amino-2-(4-methyl- 1-piperazinyl)-5-(2,3,5-trichlorophenyl) pyrimidine Corresponding author. Department of Neurology, University of Pitts- burgh, 811 Kaufman Bid., Pittsburgh, PA 15213, USA. Fax: (1) (412) 692-4636. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0006-8993(95)00868-3 but tonically inhibit Na + currents in a voltage-dependent manner and prolong inactivation of the channel [4,28]. It has been hypothesized that such agents block the patho- logic glutamate release during ischemia and have been termed 'glutamate release inhibitors'. Two observations support the hypothesis that use-dependent sodium channel antagonists are indeed pathological glutamate release in- hibitors: 1003C87 and 619C89 decrease veratrine-induced increases in extracellular glutamate in vitro and these agents decrease extracellular glutamate concentrations dur- ing focal cerebral ischemia [8,9,13,17]. However, use-de- pendent sodium channel blockers may also have other neuroprotective mechanisms. For example, since they act to prevent neuronal depolarization, these drugs may pre- vent calcium entry into the neuron via voltage-dependent calcium channels or by reversal of the Na+/Ca 2+ cotrans- porter. Recent studies have shown that the post-synaptically acting NMDA antagonist dextrorphan also decreases extra- cellular glutamate concentrations during spinal cord is- chemia and trauma [21,22]. These studies raise the ques- tion whether sodium channel blockers are indeed 'gluta- mate release inhibitors', or whether their effect upon extra- cellular glutamate is any different from other neuroprotec- tants that nonspecifically prevent glutamate release from dying cells.