Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 14 No. 4 • September 2011


Remarkable New Findings: When Fish Oils Meet
Cannabis Receptors: A Result is Powerful
Protection of the Brain Against Neuroinflammation

Here’s some really good news. Maybe even a little bit funny (read on). A remarkable new paper1 reports sensational brain protective effects of naturally formed bioactive oxygenated derived products of DHA (docosahexaenoic acid, a long chain polyunsaturated fatty acid found in fish oils). In the paper, the authors did a sophisticated analysis of a series of docosahexaenoyl ethanolamide (DHEA) products derived from DHA that have profound anti-inflammatory and organ-protective properties in the brain.

Fascinatingly, DHA (docosahexaenoic acid) is thought to be converted in the brain to DHEA (docosahexaenoyl ethanolamide) by the same pathway as N-acyl-arachidonoyl ethanolamide (AEA, anandamide), an endocannabinoid (a natural endogenous cannabinoid that activates the same receptors, CB1 and CB2, as the active ingredients in cannabis). Note: the initials DHEA are also used by scientists as an acronym to represent dehydroepiandrosterone, which is entirely different from the DHEA that is discussed in this new paper; this is unfortunate because of the danger of confusion, so keep in mind as you read this paper review that DHEA (docosahexaenoyl ethanolamide) has nothing to do with the other DHEA (dehydroepiandrosterone).

The authors1 suggest that the newly identified bioactive products from DHEA “may underlie some of the beneficial effects of DHA [docosahexaenoic acid] administration.” The experimental work was done in male FVB mice.

The paper1 reports that these newly identified enzymatic oxidation products from DHEA are activators of CB2 cannabis receptors (CB2 is a potent anti-inflammatory cannabinoid receptor that does not have psychotropic effects), with enhanced potencies that are in the nanomolar range.

The authors explained that the production of N-acyl ethanolamide is enhanced during stroke, so they examined whether DHEA had biological effects in platelet-leukocyte aggregate formation in human whole blood. “Platelet-leukocyte aggregate formation is a component of many vascular diseases, stroke, diabetes, and hypertension. Specifically, increased platelet-leukocyte aggregates were suggested as an early marker for acute myocardial infarction [heart attack] and are increasingly regarded as a cardiovascular risk factor. Also, patients with elevated circulating platelet-monocyte aggregates may reflect a pro-atherogenic phenotype [e.g., a vulnerability to develop atherosclerosis].” Moreover, they note that platelet-leukocyte aggregates stimulate the production of pro-inflammatory cyokines such as IL-1beta, IL-8, MCP-1, MIP-1b, PAF [platelet activating factor], and matrix metallopoteinase plus procoagulant tissue factors. As the authors had identified 10,17-diHDHEA and 15-HEDPEA as two major DHEA-derived products produced by isolated human PMN, they assessed the effects of these two substances in PAF (platelet activating factor)-stimulated platelet-monocyte aggregate formation. The results showed that both were potent signals and, “at concentrations as low as 10 pm [picomole, 10–12 mole], each decreased 100 nm PAF-stimulated platelet-monocyte aggregate formation ~30% in human whole blood. The 10,17-diHDHEA also decreased PAF-stimulated platelet-PMN aggregates by 25–35%.” Thus, these compounds are among the most potent biochemicals known.

The authors also assessed the effect of the DHEA-derived products on ischemia-reperfusion injury, which results when blood flow is reduced or stopped and then fully restored as in a heart attack. “[T]he prevention of PMN activation or accumulation in ischemia organ reduces tissue injury after reperfusion.” They found that 15-HEDPEA, which effectively stopped PMN chemotactic migration (neutrophil migration into ischemic tissues is responsible for much of the ischemia-reperfusion tissue damage) decreased PMN infiltration in lung by ~50%. “It is noteworthy that aberrant and excessive leukocytic infiltration is also associated with other diseases, including arthritis and psoriasis.”

Another paper2 reports that a CB2-selective agonist (activator of the CB2 cannabinoid receptor), JWH-015, reduced the migration of human monocytes in response to inflammatory signals and thus CB2 agonists may have a therapeutic effect in chronic inflammatory conditions such as atherosclerosis. In atherosclerosis, a crucial part of the process of development and progression is a result of the recruitment of inflammatory cells into the arterial intima.2

All This and Neurogenesis, Too!

Moreover, a recent paper3 found that docosahexaenoyl ethanolamide promotes the development of hippocampal neurons. “We found active biosynthesis of DEA (N-docosahexaenoyl ethanolamide) in developing hippocampi as well as the hippocampal neuronal culture. Treatment of hippocampal neurons with DEA promoted neurite growth, synaptogenesis and expression of glutamate receptor subunits and enhanced glutamatergic synaptic activity as in the case with DHA [docosahexaenoic acid], but at substantially lower concentrations. Our results suggest that DEA is an active component of DHA-mediated hippocampal development.”3 The authors3 also note that the content of docosahexaenoyl ethanolamide in the pig brain was increased by dietary inclusion of DHA (docosahexaenoic acid) as reported in a study by others.

References

  1. Yang et al. Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals. J Biol Chem 286(36):31532-41 (2011).
  2. Montecucco et al. CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol 294:H1145-55 (2008).
  3. Kim et al. N-Docosahexaenoylethanolamide promotes development of hippocampal neurons. Biochem J 435:327-36 (2011).

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