Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor.
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.
Klegeris
Andis
A
Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Westbrook Mall, Vancouver, BC, Canada V6T 1Z3.
Bissonnette
Christopher J
CJ
McGeer
Patrick L
PL
D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001892:Camphanes / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002186:Cannabinoids / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D005562:Formazans / Q000737:chemistry; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000737:chemistry; D008024:Ligands; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000473:pathology* / Q000517:prevention & control; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D013702:Temporal Lobe; D013778:Tetrazolium Salts / Q000737:chemistry
D001892:Camphanes; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D016207:Cytokines; D005562:Formazans; D007211:Indoles; D008024:Ligands; D009025:Morpholines; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D013778:Tetrazolium Salts; C471852:indomethacin morpholinylamide; C079782:MTT formazan; D013759:Dronabinol; D007770:L-Lactate Dehydrogenase; D000077285:Rimonabant; C402944:JHW 015; D007213:Indomethacin