Istradefylline prevents central nervous system oxygen toxicity

Central nervous system oxygen toxicity (CNS-OT) is a toxic reaction induced by inhalation of gases with excessively high partial pressure of oxygen, for which effective proactive preventive and therapeutic measures are currently lacking. Building on our previous work implicating adenosine A2A receptor (A2AR) signaling, we examined the prophylactic effects of istradefylline (KW-6002), an approved A2AR antagonist, in male mice. We found that pretreatment oral administration of istradefylline (0.5-20 mg/kg) in mice significantly prolonged the latency to seizure onset and markedly reduced both the intensity and frequency of seizures during a 30-min exposure to 100% oxygen at 5 ATA. Cortical targeted metabolomics showed that HBO exposure decreased GABA and increased glutamate; istradefylline increased cortical GABA without significantly reducing cortical glutamate. Separate ELISA measurements showed lower hippocampal glutamate in istradefylline-treated mice than in HBO-exposed vehicle controls, whereas reductions in the other regions examined were not statistically significant. In the striatum, istradefylline was associated with lower cAMP, immunoreactive PKA protein concentration, and phosphorylated CREB, together with reduced GluA1 Ser845 phosphorylation and increased GABA_A receptor β3 Ser408/409 phosphorylation. In the cortex, malondialdehyde levels decreased and catalase activity increased, whereas glutathione peroxidase activity decreased further. Striatal IL-1β, IL-6, and TNF-α mRNA levels were also reduced. These findings support a prophylactic effect of istradefylline against HBO-induced seizures in male mice and identify associated changes in neurotransmitter levels, receptor phosphorylation, signaling markers, oxidative-stress measures, and inflammatory-gene expression. These results provide a theoretical basis for the development of proactive preventive and therapeutic strategies for CNS-OT with potential clinical application.