Treatment with an AMPA Antagonist 12 Hours following Severe Normothermic Forebrain Ischemia Prevents CA1 Neuronal Injury

Abstract

The neuroprotective effects of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( f)quinoxaline (NBQX), GYKI 52466, and MK-801 were tested following severe forebrain ischemia. Wistar rats were subjected to 10 min of normothermic ischemia and reperfused for 7 days. Necrotic hippocampal CA1 neurons were counted and expressed as a percentage (mean ± SD). In Experiment 1, saline-treated rats sustained 81 ± 20% damage to dorsal CA1. Rats given NBQX 30 mg/kg i.p. x 3 lost 21 ± 27% (p < 0.01). Neither MK-801 1 mg i.p. x 3 alone, nor in combination with the cytoprotective dose of NBQX protected CA1, with 83 ± 18 and 54 ± 34% damage, respectively (NS). Giving NBQX 90 mg/kg i.v. did not protect cells (94 ± 5%) and resulted in nephrotoxicity. In Experiment 2, rats were given saline or three doses of NBQX 30 mg/kg i.p. immediately at reperfusion (RP) or after a 6-, 12-, or 24-h delay. Saline-treated rats suffered 79 ± 16% injury. NBQX given immediately resulted in 17 ± 17% injury, and even if treatment was delayed by either 6 or 12 h, there was marked protection with only 27 ± 32 and 25 ± 17% injury, respectively (all p < 0.01). Delaying the initiation of treatment to 24 h was not successful, resulting in 50 ± 28% injury (NS). In Experiment 3, saline-treated rats lost 81 ± 19% of CA1 cells, while those given GYKI 52466 10 mg/kg i.p. x 5 starting immediately following RP lost 80 ± 14%. Blocking α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors with NBQX postischemia is highly efficacious, indicating that delayed degeneration of CA1 cells is AMPA rather than N-methyl-d-aspartate (NMDA) receptor-linked and is reversible for CA1 cells for at least 12 h.