Motor Performance, Histologic Damage, and Calcium Influx in Rats Treated with NBQX after Focal Ischemia

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Abstract
2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo( F)-quinoxaline (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, has been reported to provide neuronal protection after global ischemia. The objectives of this study were to evaluate the neuroprotective effects of NBQX initiated after focal cortical ischemia and to validate a method for measuring functional outcome in this model. Male spontaneously hypertensive rats (SHRs) were exposed to various durations of transient or permanent tandem middle cerebral artery (MCA) occlusion. Studies compared motor performance using balance beam and prehensile-traction tests, calcium–calmodulin (Ca–CaM) binding by immunohistochemistry, and infarct volume between NBQX-treated animals [intravenous (i.v.) 5 mg/kg/h × 6 h or intraperitoneal (i.p.) 30 mg/kg q 30 min × 3 begun postischemia] and controls. All ischemic groups performed less well than sham-operated controls on the motor performance tasks in proportion to the severity of ischemia. No significant improvement in motor performance was noted in the NBQX-treated versus the control animals after 1 h or permanent MCA/CCA occlusion. Treatment with NBQX (i.v. or i.p. dosing) did not reduce Ca–CaM binding after 1 h of occlusion with 1 h of reperfusion or after 2 h of occlusion. Similarly, there was no reduction in infarct size between NBQX-treated and control animals after 24 h of permanent MCA/CCA occlusion (74.6 ±7.1 vs. 80.1 ± 6.0 ml; ns) or after 1 h of occlusion with 23 h of reperfusion (55.1 ± 4.4 vs. 47.4 ± 6.2 ml; ns). We conclude that therapy with NBQX alone has no protective effect in this model of ischemia, which may be related in part to its inability to prevent a postischemic increase in intracellular Ca in cortical neurons, and that our method of measuring motor performance is a useful indicator of functional outcome in this model.