Creatine preserves mitochondrial integrity and ameliorates early epileptiform activity and cognitive impairment via regulation of Na⁺,K⁺-ATPase in adolescent rats with severe traumatic brain injury.

In this study, we demonstrate for the first time that post-injury creatine supplementation (300 mg/kg, p.o.) administered for two weeks attenuates blood-brain barrier disruption, cortical lesion volume (by ∼60%), spatial memory deficits (reducing escape latency by ∼50% in the Barnes maze), hippocampal theta/delta rhythm alterations, and epileptiform activity in 35-day-old male rats subjected to severe fluid percussion injury (FPI). In the hippocampus, the FPI protocol did not cause overt neuronal loss-particularly of parvalbumin-positive neurons in the CA1 and CA2 regions-but it significantly reduced creatine levels and induced marked mitochondrial dysfunction. These alterations were evidenced by impaired MTT reduction, disrupted mitochondrial membrane potential (Δψ), decreased SDH activity, inhibition of respiratory chain complexes I-III, COX, citrate synthase (CS), and CKm activity, together with increased mitochondrial oxidative stress (enhanced DCFH-DA oxidation, elevated 4-hydroxynonenal levels, depletion of free -SH groups, and reduced GSH levels). We propose a mechanistic cascade wherein mitochondrial dysfunction and elevated oxidative stress drive the inhibition of Na⁺,K⁺-ATPase, which in turn contributes to neuronal hyperexcitability and cognitive deficits. Creatine's ability to maintain mitochondrial integrity directly interrupts this cascade, protecting against dysfunctions in these essential ion-gradient systems. In conclusion, post-injury creatine supplementation preserves mitochondrial function, maintains Na⁺,K⁺-ATPase activity, and prevents epileptiform activity and cognitive deficits, highlighting creatine as a promising strategy to mitigate secondary injury. However, these findings must be interpreted in light of certain limitations, including the use of a male-only cohort, a single time-point assessment, and the correlational nature of the proposed mechanistic pathways, warranting further investigation.