Creatine maintains mitochondrial integrity and protects against dysfunction in molecular systems involved in early epileptiform activity and cognitive impairment in young rats submitted to traumatic brain injury

Abstract

Abstract Despite the number of studies supporting the neuroprotective role of creatine in pathophysiology caused by traumatic brain injuries, there is insufficient knowledge of how this ergogenic compound may potentially affect brain-injury complications in adolescence. Thus, we hypothesized that creatine supplementation after a TBI could prevent from deleterious neurological effects such as memory deficits, mitochondrial disfunction and epileptiform activity. Our experimental data revealed, for the first time, that creatine supplementation (300 mg/kg, po) for two weeks after neuronal injury protected against spatial memory dysfunction (Barnes maze test), disruption of hippocampal theta/delta activity, and spontaneous epileptiform activity in 35-day-old rats submitted to severe fluid percussion injury (FPI). Interestingly, the FPI protocol did not cause cell loss (especially parvalbumin-positive neurons) in the CA1 and CA2/CA3 areas but induced mitochondria dysfunction (MTT, Δψ, SDH, complex II, COX, CS, CKm activity inhibition, and CKm immunoreactivity decrease), and mitochondrial oxidative stress (DCFH-DA oxidation, increased 4-hydroxynonenal levels, free -SH groups, and lower GSH levels). Creatine’s ability to maintain mitochondrial integrity protected against dysfunctions in molecular systems involved in cellular energy homeostasis (decreased PGC1 and TFAM immunoreactivity), Na+,K+-ATPase activity inhibition, and proteins related to brain plasticity (decreased BDNF, TrkB, and pCREB/CREB immunoreactivity) after FPI. These data suggest that epileptiform activity and cognitive dysfunction in young rats may, at least partly, result from alterations in surviving neurons interfering with creatine-induced secondary injury, which may be an excellent therapeutic strategy against toxicity induced by traumatic brain injury.