Background: The mechanisms underlying central nervous system oxygen toxicity (CNS-OT), which manifests as generalized seizures, remain poorly understood, thereby limiting the utility of hyperbaric oxygen therapy and deep-sea diving. This study investigates the distinct contributions of ionotropic N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors to hyperoxic seizure initiation and hippocampal neurodegeneration. Method: Male Wistar rats were assigned to seizure-monitoring groups (n = 86) exposed to 100% O2 at 6 ATA until seizure onset: saline control; memantine (1, 5, 25 mg/kg); perampanel (0.2, 1, 5 mg/kg); memantine + perampanel combination (5 + 1 mg/kg); and methionine sulfoximine controls (50, 100 mg/kg). For morphological analysis (NeuN immunohistochemistry, 48 h post-exposure), separate groups (n = 8 per group) were exposed to HBO2 for a fixed 30 min duration, alongside a normobaric room-air control (n = 8). Seizure latency and progression (Racine scale) were analyzed via one-way ANOVA and Tukey's test. Results: Paradoxically, NMDA receptor blockade with memantine completely failed to protect animals, significantly accelerating seizure onset (p < 0.05). Conversely, non-competitive AMPA inhibition with perampanel (1, 5 mg/kg) exerted a powerful, dose-dependent anticonvulsant effect and prevented hippocampal CA1/CA3 cell death. Perampanel co-administration completely mitigated the proconvulsant acceleration induced by memantine, demonstrating that AMPA receptor activation, rather than NMDA signaling, serves as the true primary upstream trigger for hyperoxic convulsions. Conclusion: Our findings sharply contrast with the established priority of NMDA glutamate receptors in epileptogenesis, revealing a novel neurochemical mechanism under extreme hyperoxia. We identify fast-acting AMPA receptors as the definitive principal molecular targets for mitigating CNS oxygen toxicity.
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