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Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor.

Abstract

1 Two cannabinoid receptors, CB1 and CB2, have been identified. The CB1 receptor is preferentially expressed in brain, and the CB2 receptor in cells of leukocyte lineage. We identified the mRNA for the CB1 receptor in human neuroblastoma SH-SY5Y cells, and the mRNA and protein for the CB2 receptor in human microglia and THP-1 cells. 2 Delta(9)-and Delta(8)-tetrahydrocannabinol (THC) were toxic when added directly to SH-SY5Y neuroblastoma cells. The toxicity of Delta(9)- THC was inhibited by the CB1 receptor antagonist SR141716A but not by the CB2 receptor antagonist SR144528. The endogenous ligand anandamide was also toxic, and this toxicity was enhanced by inhibitors of its enzymatic hydrolysis. 3 The selective CB2 receptor ligands JWH-015 and indomethacin morpholinylamide (BML-190), when added to THP-1 cells before stimulation with lipopolysaccharide (LPS) and IFN-gamma, reduced the toxicity of their culture supernatants to SH-SY5Y cells. JWH-015 was more effective against neurotoxicity of human microglia than THP-1 cells. The antineurotoxic activity of JWH-015 was blocked by the selective CB2 receptor antagonist SR144528, but not by the CB1 receptor antagonist SR141716A. This activity of JWH-015 was synergistic with that of the 5-lipoxygenase (5-LOX) inhibitor REV 5901. 4 Cannabinoids inhibited secretion of IL-1beta and tumor necrosis factor-alpha (TNF-alpha) by stimulated THP-1 cells, but these effects could not be directly correlated with their antineurotoxic activity. 5 Specific CB2 receptor ligands could be useful anti-inflammatory agents, while avoiding the neurotoxic and psychoactive effects of CB1 receptor ligands such as Delta(9)-THC.

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  • Authors+Show Affiliations

    ,

    Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3.

    ,

    Source

    British journal of pharmacology 139:4 2003 Jun pg 775-86

    MeSH

    Astrocytes
    Bornanes
    Cannabinoid Receptor Modulators
    Cannabinoids
    Cell Line
    Cytokines
    Dronabinol
    Formazans
    Gene Expression
    Humans
    Indoles
    Indomethacin
    L-Lactate Dehydrogenase
    Ligands
    Microglia
    Monocytes
    Morpholines
    Nerve Degeneration
    Neurotoxicity Syndromes
    Piperidines
    Pyrazoles
    RNA, Messenger
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Reverse Transcriptase Polymerase Chain Reaction
    Rimonabant
    Temporal Lobe
    Tetrazolium Salts

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    12813001

    Citation

    Klegeris, Andis, et al. "Reduction of Human Monocytic Cell Neurotoxicity and Cytokine Secretion By Ligands of the Cannabinoid-type CB2 Receptor." British Journal of Pharmacology, vol. 139, no. 4, 2003, pp. 775-86.
    Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol. 2003;139(4):775-86.
    Klegeris, A., Bissonnette, C. J., & McGeer, P. L. (2003). Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. British Journal of Pharmacology, 139(4), pp. 775-86.
    Klegeris A, Bissonnette CJ, McGeer PL. Reduction of Human Monocytic Cell Neurotoxicity and Cytokine Secretion By Ligands of the Cannabinoid-type CB2 Receptor. Br J Pharmacol. 2003;139(4):775-86. PubMed PMID: 12813001.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. AU - Klegeris,Andis, AU - Bissonnette,Christopher J, AU - McGeer,Patrick L, PY - 2003/6/19/pubmed PY - 2004/3/25/medline PY - 2003/6/19/entrez SP - 775 EP - 86 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 139 IS - 4 N2 - 1 Two cannabinoid receptors, CB1 and CB2, have been identified. The CB1 receptor is preferentially expressed in brain, and the CB2 receptor in cells of leukocyte lineage. We identified the mRNA for the CB1 receptor in human neuroblastoma SH-SY5Y cells, and the mRNA and protein for the CB2 receptor in human microglia and THP-1 cells. 2 Delta(9)-and Delta(8)-tetrahydrocannabinol (THC) were toxic when added directly to SH-SY5Y neuroblastoma cells. The toxicity of Delta(9)- THC was inhibited by the CB1 receptor antagonist SR141716A but not by the CB2 receptor antagonist SR144528. The endogenous ligand anandamide was also toxic, and this toxicity was enhanced by inhibitors of its enzymatic hydrolysis. 3 The selective CB2 receptor ligands JWH-015 and indomethacin morpholinylamide (BML-190), when added to THP-1 cells before stimulation with lipopolysaccharide (LPS) and IFN-gamma, reduced the toxicity of their culture supernatants to SH-SY5Y cells. JWH-015 was more effective against neurotoxicity of human microglia than THP-1 cells. The antineurotoxic activity of JWH-015 was blocked by the selective CB2 receptor antagonist SR144528, but not by the CB1 receptor antagonist SR141716A. This activity of JWH-015 was synergistic with that of the 5-lipoxygenase (5-LOX) inhibitor REV 5901. 4 Cannabinoids inhibited secretion of IL-1beta and tumor necrosis factor-alpha (TNF-alpha) by stimulated THP-1 cells, but these effects could not be directly correlated with their antineurotoxic activity. 5 Specific CB2 receptor ligands could be useful anti-inflammatory agents, while avoiding the neurotoxic and psychoactive effects of CB1 receptor ligands such as Delta(9)-THC. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/12813001/Reduction_of_human_monocytic_cell_neurotoxicity_and_cytokine_secretion_by_ligands_of_the_cannabinoid_type_CB2_receptor_ L2 - https://doi.org/10.1038/sj.bjp.0705304 DB - PRIME DP - Unbound Medicine ER -