Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor
Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor
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DOI：
10.1038/sj.bjp.0705304
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发表时间：
2003-06-01
影响因子：
7.3
通讯作者：
McGeer, PL
中科院分区：
文献类型：
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作者：
Klegeris, A;Bissonnette, CJ;McGeer, PL
1.已鉴定出两种大麻素受体，CB 1和CB 2。CB 1受体优先在脑中表达，而CB 2受体在白细胞谱系的细胞中表达。我们鉴定了人神经母细胞瘤SH-SY 5 Y细胞中CB 1受体的mRNA，以及人小胶质细胞和THP-1细胞中CB 2受体的mRNA和蛋白质。2当直接加入SH-SY 5 Y神经母细胞瘤细胞时，Delta（9）-和Delta（8）-四氢大麻酚（THC）是有毒的。δ（9）-THC的毒性可被CB 1受体拮抗剂SR 141716 A抑制，但不被CB 2受体拮抗剂SR 144528抑制。内源性配体花生四烯酸也是有毒的，并且这种毒性通过其酶水解的抑制剂而增强。3选择性CB 2受体配体JWH-015和吲哚美辛吗啉酰胺（BML-190）当在用脂多糖（LPS）和IFN-γ刺激之前添加到THP-1细胞中时，降低其培养上清液对SH-SY 5 Y细胞的毒性。JWH-015比THP-1细胞更有效地对抗人小胶质细胞的神经毒性。JWH-015的抗神经毒作用可被选择性CB_2受体拮抗剂SR_（144528）阻断，但不被CB_1受体拮抗剂SR_（141716）A阻断。JWH-015的这种活性与5-脂氧合酶（5-LOX）抑制剂REV 5901的活性具有协同作用。4大麻素抑制IL-1 β和肿瘤坏死因子-α的分泌（TNF-α），但这些作用不能直接与它们的抗神经毒性活性。5特异性CB 2受体配体可能是有用的抗炎剂，同时避免了CB 1受体配体如δ（9）-THC的神经毒性和精神活性作用。
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.