Sodium valproate prevents radiation-induced injury in hippocampal neurons via activation of the Nrf2/HO-1 pathway

Neuroscience. 2016 Sep 7:331:40-51. doi: 10.1016/j.neuroscience.2016.06.019. Epub 2016 Jun 17.

Abstract

Purpose: To investigate the neuroprotective role of sodium valproate (VPA) in a hippocampal neuronal cell line (HT22) and the hippocampus of zebrafish after exposure to radiation.

Methods: We investigated whether VPA could protect HT22 hippocampal neurons and the hippocampus of zebrafish from radiation-induced injury. We measured the generation of reactive oxygen species (ROS), the mitochondrial membrane potential, the levels of glutathione (GSH) and malondialdehyde (MDA), and the activity of superoxide dismutase (SOD). The expression of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was also measured. The cognitive behavior of the zebrafish was evaluated 1month after radiation exposure.

Results: VPA treatment improved the survival rate (300 mg/kg body weight (BW) VPA: 76.67%; 100 mg/kg BW VPA: 56.7%) of zebrafish 1 month after exposure to a lethal dose of whole-body irradiation (P<0.01). VPA treatment decreased the ROS generation (P<0.01), decreased the MDA levels (P<0.01), increased the GSH levels (P<0.01) and increased the SOD activity (P<0.01). VPA treatment activated the Nrf2/HO-1 pathway, increased the nuclear translocation of Nrf2 and increased the mRNA (P<0.01) and protein expression of HO-1 to prevent radiation-induced neuronal injury. SiRNA knockdown of the Nrf2 gene prevented the VPA-induced attenuation of radiation injury in the HT22 neuronal cells that was found in the control cells (40.09±1.76% vs. 41.14±1.09%, P>0.05). VPA also improved the zebrafish cognitive behavior after radiation-induced neuronal injury as measured by the exploration test (control 5.74±1.42min vs. radiation therapy 16.39±4.03min vs. radiation therapy plus VPA 7.18±1.79min, P<0.05).

Conclusions: ROS generation after radiation exposure contributes to DNA damage in the zebrafish brain. VPA inhibits ROS generation by activating the Nrf2/HO-1 pathway, which improves cognitive behavior following radiation-induced neuronal injury.

Keywords: cognitive damage; ionizing irradiation; reactive oxygen species; sodium valproate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cell Survival / radiation effects
  • Cognition / drug effects
  • Cognition / physiology
  • Cognition / radiation effects
  • Drug Evaluation, Preclinical
  • Fish Proteins / metabolism
  • Heme Oxygenase-1 / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / radiation effects
  • Membrane Proteins / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / radiation effects
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Oxidative Stress / radiation effects
  • RNA, Messenger / metabolism
  • Radiation Injuries, Experimental / metabolism
  • Radiation Injuries, Experimental / prevention & control*
  • Radiation-Protective Agents / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Valproic Acid / pharmacology*
  • Zebrafish

Substances

  • Fish Proteins
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • Radiation-Protective Agents
  • Valproic Acid
  • Heme Oxygenase-1
  • Hmox1 protein, mouse