Neuroprotective and anti-apoptotic effects of valproic acid on adult rat cerebral cortex through ERK and Akt signaling pathway at acute phase of traumatic brain injury

Brain Res. 2014 Mar 25;1555:1-9. doi: 10.1016/j.brainres.2014.01.051. Epub 2014 Feb 5.


Mood stabilizer valproic acid (VPA), a widely used antiepileptic drug that has been demonstrated neuroprotective effect against various insults through multiple signaling pathways. The role of VPA in traumatic brain injury (TBI) remains unclear. In the present study, we investigated the neuroprotective potency of VPA for protection against TBI in adult rats, focusing on studying signaling mediators of two well characterized pro-survival molecules, extracellular signal-regulated protein kinase (ERK) and Akt. We found that treatment of VPA after TBI significantly attenuated brain edema, reduced contusion volume and the rate of neuronal apoptosis. The treatment also partly blocked an increase in capase-3 activity. VPA markedly up-regulated the activity of ERK and Akt expression. Moreover, treatment with either PD98059, an ERK inhibitor and/or LY294002, an Akt inhibitor, attenuated the neuroprotection of VPA against TBI to varying degrees. Taken together, these results demonstrated that treatment with VPA after TBI could be neuroprotective via activation of ERK and Akt signaling pathways.

Keywords: Akt; Extracellular signal-regulated kinase; Neuroprotective effect; Rat; Traumatic brain injury; Valproic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Brain Injuries / drug therapy*
  • Brain Injuries / enzymology
  • Brain Injuries / pathology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / enzymology*
  • Cerebral Cortex / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Male
  • Neuroprotective Agents / therapeutic use*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Valproic Acid / therapeutic use*


  • Neuroprotective Agents
  • Valproic Acid
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases