Distinct Roles of NMDA and AMPA Receptors in the Pathogenesis of Hyperbaric Oxygen-Induced Seizures.

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.