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Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide.

Abstract

Upon activation, brain microglial cells release proinflammatory mediators, such as TNFalpha, which may play an important role in eliciting neuroinflammatory processes causing brain damage. As cannabinoids have been reported to exert anti-inflammatory and neuroprotective actions in the brain, we here examined the effect of both synthetic and endogenous cannabinoids on TNFalpha release elicited by bacterial endotoxin lypopolysaccharide (LPS) in cultured microglia. Exposure of primary cultures of rat cortical microglial cells to LPS significantly stimulated TNFalpha mRNA expression and release. The endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG), as well as the synthetic cannabinoids (+)WIN 55,212-2, CP 55,940, and HU210, inhibited in a concentration-dependent manner (1-10 microM) the LPS-induced TNFalpha release. Unlike the high-affinity cannabinoid receptor agonist (+)WIN 55,212-2, the low-affinity stereoisomer (-)WIN 55,212-2 did not exert any significant inhibition on TNFalpha release. Given this stereoselectivity, the ability of (+)WIN 55,212-2 to inhibit LPS-induced TNFalpha release from microglia is most likely receptor-mediated. By RT-PCR we found that the two G(i/o) protein-coupled cannabinoid receptors (type 1 and 2) are both expressed in microglial cultures. However, selective antagonists of type 1 (SR141716A and AM251) and type 2 (SR144528) cannabinoid receptors did not affect the effect of (+)WIN 55,212-2. Consistent with this finding is the observation that the ablative effect of (+)WIN 55,212-2 on LPS-evoked release of TNFalpha was not sensitive to the G(i/o) protein inactivator pertussis toxin. In addition, the cAMP elevating agents dibutyryl cAMP and forskolin both abolished LPS-induced TNFalpha release, thus rendering unlikely the possibility that (+)WIN 55,212-2 could ablate TNFalpha release through the inhibition of adenylate cyclase via the G(i)-coupled cannabinoid receptors type 1 and 2. In summary, our data indicate that both synthetic and endogenous cannabinoids inhibit LPS-induced release of TNFalpha from microglial cells. By showing that such effect does not appear to be mediated by either CB receptor type 1 or 2, we provide evidence suggestive of the existence of yet unidentified cannabinoid receptor(s) in brain microglia.

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  • Authors+Show Affiliations

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    Research & Innovation (R&I) Company, Padova, Italy. facchinetti@researchinnovation.com

    , , ,

    Source

    Glia 41:2 2003 Jan 15 pg 161-8

    MeSH

    Animals
    Animals, Newborn
    Anti-Inflammatory Agents
    Arachidonic Acids
    Benzoxazines
    Brain
    Cannabinoids
    Cells, Cultured
    Cyclohexanols
    Dronabinol
    Encephalitis
    Endocannabinoids
    Glycerides
    Inflammation Mediators
    Microglia
    Morpholines
    Naphthalenes
    Neuroprotective Agents
    RNA, Messenger
    Rats
    Rats, Sprague-Dawley
    Receptors, Cannabinoid
    Receptors, Drug
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    12509806

    Citation

    Facchinetti, Fabrizio, et al. "Cannabinoids Ablate Release of TNFalpha in Rat Microglial Cells Stimulated With Lypopolysaccharide." Glia, vol. 41, no. 2, 2003, pp. 161-8.
    Facchinetti F, Del Giudice E, Furegato S, et al. Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia. 2003;41(2):161-8.
    Facchinetti, F., Del Giudice, E., Furegato, S., Passarotto, M., & Leon, A. (2003). Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia, 41(2), pp. 161-8.
    Facchinetti F, et al. Cannabinoids Ablate Release of TNFalpha in Rat Microglial Cells Stimulated With Lypopolysaccharide. Glia. 2003 Jan 15;41(2):161-8. PubMed PMID: 12509806.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. AU - Facchinetti,Fabrizio, AU - Del Giudice,Elda, AU - Furegato,Sara, AU - Passarotto,Marzla, AU - Leon,Alberta, PY - 2003/1/2/pubmed PY - 2003/4/4/medline PY - 2003/1/2/entrez SP - 161 EP - 8 JF - Glia JO - Glia VL - 41 IS - 2 N2 - Upon activation, brain microglial cells release proinflammatory mediators, such as TNFalpha, which may play an important role in eliciting neuroinflammatory processes causing brain damage. As cannabinoids have been reported to exert anti-inflammatory and neuroprotective actions in the brain, we here examined the effect of both synthetic and endogenous cannabinoids on TNFalpha release elicited by bacterial endotoxin lypopolysaccharide (LPS) in cultured microglia. Exposure of primary cultures of rat cortical microglial cells to LPS significantly stimulated TNFalpha mRNA expression and release. The endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG), as well as the synthetic cannabinoids (+)WIN 55,212-2, CP 55,940, and HU210, inhibited in a concentration-dependent manner (1-10 microM) the LPS-induced TNFalpha release. Unlike the high-affinity cannabinoid receptor agonist (+)WIN 55,212-2, the low-affinity stereoisomer (-)WIN 55,212-2 did not exert any significant inhibition on TNFalpha release. Given this stereoselectivity, the ability of (+)WIN 55,212-2 to inhibit LPS-induced TNFalpha release from microglia is most likely receptor-mediated. By RT-PCR we found that the two G(i/o) protein-coupled cannabinoid receptors (type 1 and 2) are both expressed in microglial cultures. However, selective antagonists of type 1 (SR141716A and AM251) and type 2 (SR144528) cannabinoid receptors did not affect the effect of (+)WIN 55,212-2. Consistent with this finding is the observation that the ablative effect of (+)WIN 55,212-2 on LPS-evoked release of TNFalpha was not sensitive to the G(i/o) protein inactivator pertussis toxin. In addition, the cAMP elevating agents dibutyryl cAMP and forskolin both abolished LPS-induced TNFalpha release, thus rendering unlikely the possibility that (+)WIN 55,212-2 could ablate TNFalpha release through the inhibition of adenylate cyclase via the G(i)-coupled cannabinoid receptors type 1 and 2. In summary, our data indicate that both synthetic and endogenous cannabinoids inhibit LPS-induced release of TNFalpha from microglial cells. By showing that such effect does not appear to be mediated by either CB receptor type 1 or 2, we provide evidence suggestive of the existence of yet unidentified cannabinoid receptor(s) in brain microglia. SN - 0894-1491 UR - https://www.unboundmedicine.com/medline/citation/12509806/Cannabinoids_ablate_release_of_TNFalpha_in_rat_microglial_cells_stimulated_with_lypopolysaccharide_ L2 - https://doi.org/10.1002/glia.10177 DB - PRIME DP - Unbound Medicine ER -