Accession Number:

ADA627359

Title:

A Preliminary Model for the Protective Role of the Endocannabinoid 2-Arachydonylglycerol in Neuroinflammation

Descriptive Note:

Final rept. Oct 2012-Jul 2015

Corporate Author:

HENRY M JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE WRIGHT-PATTERSON AFB OH

Report Date:

2015-09-30

Pagination or Media Count:

27.0

Abstract:

Activation of cannabinoid receptors CB1 in neurons and CB2 in immune cells by their primary endogenous ligand 2-arachidonylglycerol 2-AG, is both anti-excitatory and anti-inflammatory. Levels of 2-AG are tightly maintained by monoacylglycerol lipase MAGL, which converts 2-AG into arachidonic acid AA, and may be the main regulator of AA. Both AA and 2-AG are precursors of inflammatory prostaglandins via cyclooxygenase-2 COX2 metabolism, which is in turn inhibited by 2-AG binding to neuronal CB1 receptors. Selective MAGL inhibitors have the potential to reduce inflammation. Conversely, excessive MAGL inhibition could lead to immune suppression and an ineffective response to infection. We developed a model of 2-AG metabolism and signaling which describes prostaglandin PG production, MAGL activity, 2-AG synthesis rate, COX2 activity, neuronal CB1 receptor densities, and binding of 2-AG to CB1 receptors. The model is used to describe the effect of MAGL inhibitor JZL-184 on 2-AG, AA, and prostaglandin levels as a result of exposure to lipopolysaccharides LPS and organophosphates. The model can be extended to include 2-AG binding to CB2 receptors in immune cells modulating cytokine release, and thereby describe a hypothetical lumped immune response to a biological agent. Model simulations of normal immune responses show removal of the infectious agent with little overshoot of immune cells inflammation. Reducing the immune response by inhibiting MAGL activity may result in ineffective removal of the agent, while increasing the immune response may lead to rapid removal of the agent at the expense of a potentially damaging immune overshoot indicative of chronic inflammation.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE