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

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.

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Document Details

Document Type
Technical Report
Publication Date
Sep 30, 2015
Accession Number
ADA627359

Entities

People

  • David R. Mattie
  • Elaine A. Merrill
  • Peter J. Robinson

Organizations

  • Henry M. Jackson Foundation for the Advancement of Military Medicine

Tags

Communities of Interest

  • Materials and Manufacturing Processes

DTIC Thesaurus Topics

  • Air Force Research Laboratories
  • Alzheimer Disease
  • Biological Factors
  • Brain
  • Cells
  • Diseases And Disorders
  • Fatty Acids
  • Immune System
  • Infection
  • Inhibition
  • Inhibitors
  • Metabolism
  • Multiple Sclerosis
  • Neurodegeneration
  • Organophosphates
  • Simulations
  • Wound Infections

Fields of Study

  • Biology
  • Medicine

Readers

  • Immunology and Pathology
  • Materials Science and Engineering.
  • Molecular and Cellular Biochemistry