Post-injury oral creatine at 300 mg/kg for two weeks produced striking neuroprotection in adolescent rats subjected to severe fluid percussion injury: cortical lesion volume shrank by ~60%, spatial memory escape latency dropped ~50% in the Barnes maze, and epileptiform EEG activity was substantially attenuated. Mechanistically, creatine reversed hippocampal mitochondrial collapse — restoring membrane potential, SDH and citrate synthase activity, respiratory chain complexes I–III, and COX function — while normalizing oxidative stress markers including 4-hydroxynonenal, GSH depletion, and DCFH-DA oxidation. The authors propose a cascade: mitochondrial failure → oxidative stress → Na⁺/K⁺-ATPase inhibition → neuronal hyperexcitability and memory loss, with creatine interrupting the chain at the mitochondrial node.
The Na⁺/K⁺-ATPase angle is the most analytically interesting element here. This pump consumes roughly 40% of neuronal ATP, making it an exquisitely sensitive readout of energetic crisis — and a plausible epileptogenesis driver rarely foregrounded in TBI literature. Creatine's role as a phosphate buffer for rapid ATP regeneration makes the mechanistic chain biologically coherent rather than merely correlational.
Practical translation, however, requires caution. The model is exclusively adolescent male rats, a single post-injury supplementation window was tested, and the mechanistic pathways remain correlational — causality between Na⁺/K⁺-ATPase rescue and seizure suppression is inferred, not proven. Human TBI dosing equivalents would be substantially lower per kg body weight. Still, for a compound already regarded as safe and widely available, these effect sizes justify accelerated clinical investigation in pediatric and young-adult TBI populations. Incremental? No — this reframes creatine from ergogenic aid to plausible acute neuroprotectant with a defined ionic mechanism.