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Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection.

Abstract

Focal cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because of harmful mediators diffusing from the original lesion site. Evidence suggests that healthy cells surrounding these lesions attempt to protect themselves by producing endocannabinoids (eCBs) and activating cannabinoid receptors, the molecular target for marijuana-derived compounds. Indeed, activation of cannabinoid receptors reduces the production and diffusion of harmful mediators. Here, we provide evidence that an exception to this pattern is found in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that cell damage induced by EAE does not lead to increase in eCBs, even though cannabinoid receptors are functional because synthetic cannabinoid agonists are known to confine EAE-induced lesions. This lack of eCB increase is likely due to IFN-gamma, which is released by primed T cells invading the CNS. We show that IFN-gamma disrupts the functionality of purinergic P2X7 receptors, a key step controlling eCB production by microglia, the main source of eCBs in brain. Accordingly, induction of EAE in P2X7-/- mice results in even lower eCB levels and more pronounced cell damage than in wild-type mice. Our data suggest that the high level of CNS IFN-gamma associated with EAE disrupts eCB-mediated neuroprotection while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat multiple sclerosis.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Anesthesiology, Comparative Medicine, University of Washington, Seattle, WA 98195, USA.

    , , , , , , ,

    Source

    MeSH

    Animals
    Cannabinoid Receptor Agonists
    Cannabinoid Receptor Modulators
    Central Nervous System
    Encephalomyelitis, Autoimmune, Experimental
    Endocannabinoids
    Interferon-gamma
    Mice
    Mice, Mutant Strains
    Microglia
    Multiple Sclerosis
    Neuroprotective Agents
    Receptors, Cannabinoid
    Receptors, Purinergic P2
    Receptors, Purinergic P2X7
    T-Lymphocytes

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    16571660

    Citation

    Witting, Anke, et al. "Experimental Autoimmune Encephalomyelitis Disrupts Endocannabinoid-mediated Neuroprotection." Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 16, 2006, pp. 6362-7.
    Witting A, Chen L, Cudaback E, et al. Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc Natl Acad Sci USA. 2006;103(16):6362-7.
    Witting, A., Chen, L., Cudaback, E., Straiker, A., Walter, L., Rickman, B., ... Stella, N. (2006). Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proceedings of the National Academy of Sciences of the United States of America, 103(16), pp. 6362-7.
    Witting A, et al. Experimental Autoimmune Encephalomyelitis Disrupts Endocannabinoid-mediated Neuroprotection. Proc Natl Acad Sci USA. 2006 Apr 18;103(16):6362-7. PubMed PMID: 16571660.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. AU - Witting,Anke, AU - Chen,Lanfen, AU - Cudaback,Eiron, AU - Straiker,Alex, AU - Walter,Lisa, AU - Rickman,Barry, AU - Möller,Thomas, AU - Brosnan,Celia, AU - Stella,Nephi, Y1 - 2006/03/29/ PY - 2006/3/31/pubmed PY - 2006/6/24/medline PY - 2006/3/31/entrez SP - 6362 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 103 IS - 16 N2 - Focal cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because of harmful mediators diffusing from the original lesion site. Evidence suggests that healthy cells surrounding these lesions attempt to protect themselves by producing endocannabinoids (eCBs) and activating cannabinoid receptors, the molecular target for marijuana-derived compounds. Indeed, activation of cannabinoid receptors reduces the production and diffusion of harmful mediators. Here, we provide evidence that an exception to this pattern is found in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that cell damage induced by EAE does not lead to increase in eCBs, even though cannabinoid receptors are functional because synthetic cannabinoid agonists are known to confine EAE-induced lesions. This lack of eCB increase is likely due to IFN-gamma, which is released by primed T cells invading the CNS. We show that IFN-gamma disrupts the functionality of purinergic P2X7 receptors, a key step controlling eCB production by microglia, the main source of eCBs in brain. Accordingly, induction of EAE in P2X7-/- mice results in even lower eCB levels and more pronounced cell damage than in wild-type mice. Our data suggest that the high level of CNS IFN-gamma associated with EAE disrupts eCB-mediated neuroprotection while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat multiple sclerosis. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/16571660/Experimental_autoimmune_encephalomyelitis_disrupts_endocannabinoid_mediated_neuroprotection_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16571660 DB - PRIME DP - Unbound Medicine ER -