Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid-induced rat autism model

Int J Dev Neurosci. 2016 Apr:49:67-78. doi: 10.1016/j.ijdevneu.2015.11.006. Epub 2015 Nov 27.


Prenatal exposure to valproic acid (VPA) in rat offspring is capable of inducing experimental autism with neurobehavioral aberrations. This study investigated the effect of docosahexaenoic acid (DHA) on hippocampal cell death, learning and memory alteration in an experimental rat autism model. We found that DHA supplementation (75, 150 or 300 mg/kg/day, 21 days) rescued the VPA (600 mg/kg) induced DHA reduction in plasma and hippocampus in a dose-dependent manner, increased the levels of hippocampal p-CaMKII and p-CREB without affecting total protein level, and altered BDNF-AKT-Bcl-2 signaling pathway, as well as inhibited the activity of caspase-3. DHA also influenced the content of malondialdehyde (MDA) and the activities of antioxidant enzymes in the VPA-treated offspring. Consistent with the previous results, we also observed that 300 mg/kg DHA supplementation markedly increased the cell survival, decreased the cell apoptosis, and increased mature neuronal cell in the hippocampus in VPA-treated offspring. Utilizing the Morris water maze test, we found that DHA prevented cognitive impairment in offspring of VPA-treated rats. The data suggested that DHA may play a neuroprotective role in hippocampal neuronal cell and ameliorates dysfunctions in learning and memory in this rat autism model. Thus, DHA could be used as treatment intervention for mitigating behavioral dysfunctions in autism spectrum disorder (ASD).

Keywords: Autism; Docosahexaenoic acid (DHA); Hippocampal cell; Learning impairment; Memory impairment; Neuroprotective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / toxicity
  • Autistic Disorder / chemically induced*
  • Autistic Disorder / complications
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Disease Models, Animal
  • Docosahexaenoic Acids / metabolism
  • Docosahexaenoic Acids / therapeutic use*
  • Female
  • Glutathione Peroxidase / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Learning Disabilities* / drug therapy
  • Learning Disabilities* / etiology
  • Learning Disabilities* / pathology
  • Male
  • Malondialdehyde / metabolism
  • Maze Learning / drug effects
  • Memory Disorders* / drug therapy
  • Memory Disorders* / etiology
  • Memory Disorders* / pathology
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Phosphopyruvate Hydratase / metabolism
  • Rats
  • Rats, Wistar
  • Superoxide Dismutase / metabolism
  • Valproic Acid / toxicity


  • Anticonvulsants
  • Neuroprotective Agents
  • Docosahexaenoic Acids
  • Malondialdehyde
  • Valproic Acid
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Caspase 3
  • Phosphopyruvate Hydratase