Abstract
Endocannabinoids are released after brain injury and believed to attenuate neuronal damage by binding to CB(1) receptors and protecting against excitotoxicity. Such excitotoxic brain lesions initially result in primary destruction of brain parenchyma, which attracts macrophages and microglia. These inflammatory cells release toxic cytokines and free radicals, resulting in secondary neuronal damage. In this study, we show that the endocannabinoid system is highly activated during CNS inflammation and that the endocannabinoid anandamide (AEA) protects neurons from inflammatory damage by CB(1/2) receptor-mediated rapid induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) in microglial cells associated with histone H3 phoshorylation of the mkp-1 gene sequence. As a result, AEA-induced rapid MKP-1 expression switches off MAPK signal transduction in microglial cells activated by stimulation of pattern recognition receptors. The release of AEA in injured CNS tissue might therefore represent a new mechanism of neuro-immune communication during CNS injury, which controls and limits immune response after primary CNS damage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Arachidonic Acids / metabolism*
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Arachidonic Acids / pharmacology
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Cannabinoid Receptor Modulators / metabolism*
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Cannabinoid Receptor Modulators / pharmacology
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Cell Cycle Proteins / biosynthesis*
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Cell Survival
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Cells, Cultured
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Dual Specificity Phosphatase 1
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Encephalitis / pathology
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Encephalitis / physiopathology*
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Encephalitis / prevention & control
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Endocannabinoids*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Immediate-Early Proteins / biosynthesis*
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MAP Kinase Signaling System / drug effects
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Mice
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Microglia / metabolism*
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Middle Aged
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Multiple Sclerosis / metabolism
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Multiple Sclerosis / pathology
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Neurons / pathology
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Neuroprotective Agents / metabolism*
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Neuroprotective Agents / pharmacology
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide Synthase / antagonists & inhibitors
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Phosphoprotein Phosphatases / biosynthesis*
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Phosphorylation / drug effects
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Polyunsaturated Alkamides
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / biosynthesis*
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Rats
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Rats, Wistar
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Receptors, Cannabinoid / metabolism
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Tissue Distribution
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Cell Cycle Proteins
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Endocannabinoids
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Immediate-Early Proteins
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Neuroprotective Agents
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
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Nitric Oxide
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Nitric Oxide Synthase
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Extracellular Signal-Regulated MAP Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse
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Dusp1 protein, rat
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Protein Tyrosine Phosphatases
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anandamide