Delayed creatine supplementation counteracts reduction of GABAergic function and protects against seizures susceptibility after traumatic brain injury in rats

Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8:92:328-338. doi: 10.1016/j.pnpbp.2019.02.004. Epub 2019 Feb 8.


Traumatic brain injury (TBI) is a devastating disease frequently followed by behavioral disabilities including post-traumatic epilepsy (PTE). Although reasonable progress in understanding its pathophysiology has been made, treatment of PTE is still limited. Several studies have shown the neuroprotective effect of creatine in different models of brain pathology, but its effects on PTE is not elucidated. Thus, we decided to investigate the impact of delayed and chronic creatine supplementation on susceptibility to epileptic seizures evoked by pentylenetetrazol (PTZ) after TBI. Our experimental data revealed that 4 weeks of creatine supplementation (300 mg/kg, p.o.) initiated 1 week after fluid percussion injury (FPI) notably increased the latency to first myoclonic and tonic-clonic seizures, decreased the time spent in tonic-clonic seizure, seizure intensity, epileptiform discharges and spindle oscillations induced by a sub-convulsant dose of PTZ (35 mg/kg, i.p.). Interestingly, this protective effect persists for 1 week even when creatine supplementation is discontinued. The anticonvulsant effect of creatine was associated with its ability to reduce cell loss including the number of parvalbumin positive (PARV+) cells in CA3 region of the hippocampus. Furthermore, creatine supplementation also protected against the reduction of GAD67 levels, GAD activity and specific [3H]flunitrazepam binding in the hippocampus. These findings showed that chronic creatine supplementation may play a neuroprotective role on brain excitability by controlling the GABAergic function after TBI, providing a possible new strategy for the treatment of PTE.

Keywords: Creatine; Epilepsy; Epileptiform discharge; Fluid percussion injury; GABA; Seizure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries, Traumatic / complications*
  • Brain Injuries, Traumatic / drug therapy
  • Brain Injuries, Traumatic / pathology
  • Brain Waves / drug effects
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / pathology
  • Cell Death / drug effects
  • Creatine / pharmacology*
  • Creatine / therapeutic use
  • Epilepsy, Post-Traumatic / complications*
  • Epilepsy, Post-Traumatic / drug therapy
  • Epilepsy, Post-Traumatic / prevention & control*
  • Flunitrazepam / metabolism
  • GABAergic Neurons / drug effects*
  • Glutamate Decarboxylase / metabolism
  • Male
  • Neuroprotective Agents / therapeutic use
  • Pentylenetetrazole
  • Radioligand Assay
  • Rats
  • Seizures / chemically induced
  • Seizures / complications*
  • Seizures / prevention & control*
  • Time Factors
  • Tritium / metabolism


  • Neuroprotective Agents
  • Tritium
  • Flunitrazepam
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • Creatine
  • Pentylenetetrazole