Gelsemine and koumine, principal active ingredients of Gelsemium, exhibit mechanical antiallodynia via spinal glycine receptor activation-induced allopregnanolone biosynthesis

被引:30
作者
Shoaib, Rana Muhammad [1 ]
Zhang, Jing-Yang [1 ]
Mao, Xiao-Fang [1 ]
Wang, Yong-Xiang [1 ]
机构
[1] Shanghai Jiao Tong Univ, Kings Lab, Sch Pharm, 800 Dongchuan Rd, Shanghai 200240, Peoples R China
基金
中国国家自然科学基金;
关键词
Gelsemine; Koumine; Glycine receptor; 3; alpha-HSOR; Allopregnanolone; 3-ALPHA-HYDROXYSTEROID OXIDOREDUCTASE EXPRESSION; NEUROPATHIC PAIN; COGNITIVE IMPAIRMENT; ELEGANS BENTH; MOUSE MODEL; RAT MODEL; NEUROSTEROIDS; MINOCYCLINE; STRYCHNINE; INHIBITION;
D O I
10.1016/j.bcp.2019.01.014
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Gelsemine, the principal active alkaloid from Gelsemium sempervirens Ait., and koumine, the most dominant alkaloids from Gelsemium elegans Benth., produced antinociception in a variety of rodent models of painful hypersensitivity. The present study explored the molecular mechanisms underlying gelsemine- and koumine-induced mechanical antiallodynia in neuropathic pain. The radioligand binding and displacement assays indicated that gelsemine and koumine, like glycine, were reversible and orthosteric agonists of glycine receptors with full efficacy and probably acted on same binding site as the glycine receptor antagonist strychnine. Treatment with gelsemine, koumine and glycine in primary cultures of spinal neurons (but not microglia or astrocytes) concentration dependently increased 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) mRNA expression, which was inhibited by pretreatment with strychnine but not the glial inhibitor minocycline. Intrathecal injection of gelsemine, koumine and glycine stimulated 3 alpha-HSOR mRNA expression in the spinal cords of neuropathic rats and produced mechanical antiallodynia. Their spinal mechanical antiallodynia was completely blocked by strychnine, the selective 3 alpha-HSOR inhibitor medroxyprogesterone acetate (MPA), 3 alpha-HSOR gene silencer siRNA/3 alpha-HSOR and specific GABA(A) receptor antagonist isoallopregnanolone, but not minocycline. All the results taken together uncovered that gelsemine and koumine are orthosteric agonists of glycine receptors, and produce mechanical antiallodynia through neuronal glycine receptor/3 alpha-HSOR/allopregnanolone/GABA(A) receptor pathway.
引用
收藏
页码:136 / 148
页数:13
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