The ω-3 endocannabinoid docosahexaenoyl ethanolamide reduces seizure susceptibility in mice by activating cannabinoid type 1 receptors

Brain Res Bull. 2021 May;170:74-80. doi: 10.1016/j.brainresbull.2021.02.011. Epub 2021 Feb 10.


Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most recognized omega-3 unsaturated fatty acids showing neuroprotective activity in animal and clinical studies. Docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) are non-oxygenated endogenous metabolites of DHA and EPA, which might be in charge of the anti-seizure activity of the parent molecules. We examined the effect of these metabolites on the threshold of clonic seizures induced by pentylenetetrazole (PTZ). DHEA and EPEA possess similar chemical structure to the endogenous cannabinoids. Therefore, involvement of cannabinoid (CB) receptors in the anti-seizure effect of these metabolites was also investigated. DHA, DHEA, EPEA, AM251 (CB1 receptor antagonist), and AM630 (CB2 receptor antagonist) were administered to mice by intracerebroventricular (i.c.v.) route. Threshold of clonic seizures was determined 10 and/or 15 min thereafter by intravenous infusion of PTZ. The effect of DHA and DHEA on seizure threshold was then determined in mice, which were pretreated with AM251 and/or AM630. DHA (300μM), and DHEA (100 and 300 μM) significantly increased seizure threshold, 15 (p < 0.05) and 10 min (p < 0.01) after administration, respectively. DHEA was more potent than its parent lipid, DHA in decreasing seizure susceptibility. EPEA (300 and 1000 μM) did not change seizure threshold. AM251 fully prevented the increasing effect of DHA and DHEA on seizure threshold (p < 0.05). AM630 did not inhibit the effect of DHA and DHEA on seizure threshold. This is the first report indicating that DHEA but not EPEA, possesses anti-seizure action via activating CB1 receptors. DHEA is more potent than its parent ω-3 fatty acid DHA in diminishing seizure susceptibility.

Keywords: Endocannabinoids; Ethanolamide derivative; Seizure threshold; ω-3 fatty acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoid Receptor Antagonists / pharmacology
  • Docosahexaenoic Acids / pharmacology
  • Fatty Acids, Omega-3 / pharmacology*
  • Indoles / pharmacology
  • Male
  • Mice
  • Pentylenetetrazole
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / agonists*
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Seizures / metabolism


  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Fatty Acids, Omega-3
  • Indoles
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Docosahexaenoic Acids
  • AM 251
  • iodopravadoline
  • Pentylenetetrazole