科研之友
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摘要
Neuropathic pain is a maladaptive immune response to peripheral nerve injury that causes a chronic painful condition refractory to most analgesics. Nitric oxide (NO), which is produced by nitric oxide synthases (NOSs), has been implicated as a key factor in the pathogenesis of neuropathic pain. beta-Carbolines are a large group of natural and synthetic indole alkaloids, some of which block activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B), a predominant transcriptional regulator of NOS expression. Here, we characterize the inhibitory effects of a novel 6-chloro-8-(glycinyl)-amino-beta-carboline (8-Gly carb) on NO formation and NF-kappa B activation in macrophages. 8-Gly carb was significantly more potent than the NOS inhibitor NG-nitro-Larginine methyl ester in inhibiting constitutive and inducible NO formation in primary rat macrophages. 8-Gly carb interfered with NF-kappa B-mediated gene expression in differentiated THP1-XBlue cells, a human NF-kappa B reporter macrophage cell line, but only at concentrations severalfold higher than needed to significantly inhibit NO production. 8-Gly carb also had no effect on tumor necrosis factor alpha (TNF alpha)-induced phosphorylation of the p38 mitogen-activated protein kinase in differentiated THP1 cells, and did not inhibit lipopolysaccharide- or TNF alpha-stimulated expression of TNF alpha and interleukin-1 beta. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of NOS, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible NO formation independent of NF-kappa B activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain mediated by macrophage-derived NO without interfering with cytokine expression required for neural recovery following peripheral nerve injury.
- 出版日期2015-3
