Effects of DHA on Hippocampal Autophagy and Lysosome Function After Traumatic Brain Injury

Mol Neurobiol. 2018 Mar;55(3):2454-2470. doi: 10.1007/s12035-017-0504-8. Epub 2017 Apr 1.


Traumatic brain injury (TBI) triggers endoplasmic reticulum (ER) stress and impairs autophagic clearance of damaged organelles and toxic macromolecules. In this study, we investigated the effects of the post-TBI administration of docosahexaenoic acid (DHA) on improving hippocampal autophagy flux and cognitive functions of rats. TBI was induced by cortical contusion injury in Sprague-Dawley rats, which received DHA (16 mg/kg in DMSO, intraperitoneal administration) or vehicle DMSO (1 ml/kg) with an initial dose within 15 min after the injury, followed by a daily dose for 3 or 7 days. First, RT-qPCR reveals that TBI induced a significant elevation in expression of autophagy-related genes in the hippocampus, including SQSTM1/p62 (sequestosome 1), lysosomal-associated membrane proteins 1 and 2 (Lamp1 and Lamp2), and cathepsin D (Ctsd). Upregulation of the corresponding autophagy-related proteins was detected by immunoblotting and immunostaining. In contrast, the DHA-treated rats did not exhibit the TBI-induced autophagy biogenesis and showed restored CTSD protein expression and activity. T2-weighted images and diffusion tensor imaging (DTI) of ex vivo brains showed that DHA reduced both gray matter and white matter damages in cortical and hippocampal tissues. DHA-treated animals performed better than the vehicle control group on the Morris water maze test. Taken together, these findings suggest that TBI triggers sustained stimulation of autophagy biogenesis, autophagy flux, and lysosomal functions in the hippocampus. Swift post-injury DHA administration restores hippocampal lysosomal biogenesis and function, demonstrating its therapeutic potential.

Keywords: Autophagy; Cortical contusion injury; Docosahexaenoic acid; Lysosome; Microglial polarization; Secondary injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Brain Injuries, Traumatic / drug therapy*
  • Brain Injuries, Traumatic / metabolism*
  • Brain Injuries, Traumatic / pathology
  • Docosahexaenoic Acids / pharmacology
  • Docosahexaenoic Acids / therapeutic use*
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Lysosomes / drug effects
  • Lysosomes / physiology*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Treatment Outcome


  • Docosahexaenoic Acids