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Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity.

Abstract

The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB1 agonist AM356 (R-methanandamide). AM374/AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB1-linked MAPK signaling, and (3) were blocked by a selective CB1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

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  • Authors+Show Affiliations

    ,

    Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.

    , , ,

    Source

    MeSH

    Amidohydrolases
    Animals
    Arachidonic Acids
    Biological Transport
    Cannabinoid Receptor Modulators
    Endocannabinoids
    Enzyme Inhibitors
    Excitatory Amino Acid Agonists
    Hippocampus
    Neuroprotective Agents
    Rats
    Rats, Sprague-Dawley
    Receptor, Cannabinoid, CB1

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    16120783

    Citation

    Karanian, David A., et al. "Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects Against Excitotoxicity." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 25, no. 34, 2005, pp. 7813-20.
    Karanian DA, Brown QB, Makriyannis A, et al. Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. J Neurosci. 2005;25(34):7813-20.
    Karanian, D. A., Brown, Q. B., Makriyannis, A., Kosten, T. A., & Bahr, B. A. (2005). Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 25(34), pp. 7813-20.
    Karanian DA, et al. Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects Against Excitotoxicity. J Neurosci. 2005 Aug 24;25(34):7813-20. PubMed PMID: 16120783.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. AU - Karanian,David A, AU - Brown,Queenie B, AU - Makriyannis,Alexandros, AU - Kosten,Therese A, AU - Bahr,Ben A, PY - 2005/8/27/pubmed PY - 2006/3/4/medline PY - 2005/8/27/entrez SP - 7813 EP - 20 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 25 IS - 34 N2 - The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB1 agonist AM356 (R-methanandamide). AM374/AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB1-linked MAPK signaling, and (3) were blocked by a selective CB1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/16120783/Dual_modulation_of_endocannabinoid_transport_and_fatty_acid_amide_hydrolase_protects_against_excitotoxicity_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=16120783 DB - PRIME DP - Unbound Medicine ER -