Unbound MEDLINE

Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults.

Abstract

While endocannabinoid modulation of both GABAergic and glutamatergic synaptic transmission and plasticity has been extensively investigated, our understanding of the role of endocannabinoids in protecting neurons from harmful insults remains limited. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous ligand and a full agonist for cannabinoid receptors, exhibits anti-inflammatory and neuroprotective effects via a CB1 receptor (CB1R)-mediated mechanism. However, it is still not clear whether 2-AG is also able to protect neurons from β-amyloid (Aβ)-induced neurodegeneration. Here, we demonstrate that exogenous application of 2-AG significantly protected hippocampal neurons in culture against Aβ-induced neurodegeneration and apoptosis. This neuroprotective effect was blocked by SR141716 (SR-1), a selective CB1R antagonist, but not by SR144528 (SR-2), a selective CB2R antagonist, or capsazepine (CAP), a selective transient receptor potential cation channels, subfamily V, member 1 (TRPV1) receptor antagonist. To determine whether endogenous 2-AG is capable of protecting neurons from Aβ insults, hippocampal neurons in culture were treated with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), the enzyme hydrolyzing 2-AG. MAGL inhibition that elevates endogenous levels of 2-AG also significantly reduced Aβ-induced neurodegeneration and apoptosis. The 2-AG-produced neuroprotective effects appear to be mediated via CB1R-dependent suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) phosphorylation and cyclooxygenase-2 (COX-2) expression. Our results suggest that elevation of endogenous 2-AG by inhibiting its hydrolysis has potential as a novel efficacious therapeutic approach for preventing, ameliorating or treating Alzheimer's disease.

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  • Authors

    Chen X, Zhang J, Chen C

    Source

    Neuroscience 178: 2011 Mar 31 pg 159-68

    MeSH

    Amyloid beta-Peptides
    Animals
    Apoptosis
    Arachidonic Acids
    Benzodioxoles
    Biphenyl Compounds
    Bornanes
    Cannabinoid Receptor Antagonists
    Cannabinoid Receptor Modulators
    Capsaicin
    Cell Culture Techniques
    Drug Interactions
    Endocannabinoids
    Glycerides
    Hippocampus
    Monoacylglycerol Lipases
    Nerve Degeneration
    Peptide Fragments
    Piperidines
    Pyrazoles
    Rats
    Rats, Sprague-Dawley
    Signal Transduction

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21256197