上海交大教授获新药研究新成果

　　

生物通报道：来自上海交通大学药学院的研究人员获得了神经源性疼痛调节研究的重要突破：首次发现并证明脊髓D-型氨基酸氧化酶是一个治疗神经源性疼痛的新靶点分子。

D-型氨基酸氧化酶是第一次由中国学者发现的慢性疼痛药物治疗靶点，相关研究论文发表在《Journal of Pharmacology and Experimental Therapeutics》和《Cellular and Molecular Neurobiology》上，并应邀在日本举行的D-型氨基酸国际学术研讨会和中国第10届药理学大会作大会专题报告，引起很大反响。

领导这一研究的是王永祥教授，其早年毕业于安徽医科大学，后赴加拿大留学获加拿大不列颠哥伦比亚大学药理学博士学位，并在美国斯坦福大学从事博士后研究。在美国医药公司从事新药研发多年,发表SCI论文36篇。现任上海交通大学药学院教授，博导，研究领域为药物代谢动力学，血管药理学，疼痛药理学和肿瘤药理学。这项研究得到了国家自然科学基金等的资助，其中神经源性慢性疼痛靶点研究还得到国家新药创制大平台项目的资助。

神经源性慢性疼痛由外周和中枢神经损伤所导致，涉及众多病人（约0.3%人群），目前缺乏有效及特异性的干预治疗手段，因此寻找和发现治疗神经源性慢性疼痛的新靶点和新型镇痛药物研发，一直是神经生物学研究的热点。

在这篇文章中，王永祥教授研究团队采用基因敲除/变异技术、脊髓组织基因表达技术和酶活性抑制技术等方法，研究了脊髓D-型氨基酸氧化酶在神经源性慢性疼痛中作用，对欧美传统学术观点和日本学者的结论提出了挑战，证明脊髓D-型氨基酸氧化酶是治疗神经源性慢性疼痛的新靶点分子，并得到国际承认，正如世界药理学顶尖杂志《Journal of Pharmacology and Experimental Therapeutics》认为：“该研究及时地为神经源性慢性疼痛作用机制的认识和设计治疗神经源性慢性疼痛新方法，提供了创新性思路”。

（生物通：万纹）

附：

王永祥 教授
传真： 6282-7284 Email： [e-mail]

王永祥就读于安徽医科大学，分别获医学学士学位和药理学硕士学位。后赴加拿大留学获加拿大不列颠哥伦比亚大学药理学博士学位，并在美国斯坦福大学从事博士后研究。在美国医药公司从事新药研发多年,发表SCI论文36篇。现任上海交通大学药学院教授，博导，研究领域为药物代谢动力学，血管药理学，疼痛药理学和肿瘤药理学。

研究成果（主要论著）：336260 37
28. Cheng X., Wang Y.-X. & Pang C.C.Y. (1997). Biological activation of NG-nitro-D-arginine by kidney homogenate. Naunyn-Schmiedeberg’s Arch Pharmacol.. 356: 495-499.
29. Wang Y.-X., Bezprozvannaya S., Bowersox S.S., Nadasdi L., Miljanich G., Mezo G., Silva D., Tarczy-Homoch K. & Luther R.R. (1998). Peripheral versus central potencies of N-type voltage sensitive calcium channel blockers. Naunyn-Schmiedeberg’s Arch Pharmacol., 357: 159-168.
30. Wang Y.-X., Cheng X. & Pang C.C.Y. (1998). Bilateral kidney ligation abolishes pressor response to NG-nitro-D-arginine. Eur. J. Pharmacol., 366: 175-179.
31. Hu L.-Y., Ryder T., Rafferty M.F., Feng R., Lorarski S.M., Rock D.M., Sinz M., Stoehr S.J., Taylor C.P., Weber M.L., Bowersox S.S, Miljanich, G.P., Millerman E., Wang Y.-X. & Szoke B.G.(1999). Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. J. Med. Chem. 42: 4239-4249.
32. Wang Y.-X., Bowersox S.S. Pettus M. & Gao G. (1999). Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 291: 1008-1016.
33. Song Y.T., Bowersox S.S., Connor D., Dooley D.J., Lotarski S.M., Malone T., Miljanich G., Millerman E., Rafferty M.F., Rock D., Roth B.D., Schmidt J., Stoehr S., Szoke B.G., Taylor C., Vartanian M. & Wang Y.-X. (2000). (S)-4-methyl-2-(methylamino) pentanoic acid {4,4-bis (4-flurophenyl) butyl] amide hydrochloride, a novel calcium channel antagonist, is efficacious in several animal models of pain. J. Med. Chem. 43: 3474-3477.
34. Wang Y.-X., Legzdins P, Poon JS & Pang CC Poon C.I. & Pang, C.C.Y. (2000). Vasodilator effects of organotransition-metal nitrosyl complexes, novel nitric oxide donors. J. Cardiovascular Pharmacol.35: 73-77.
35. Wang Y.-X., Pettus M., Gao D., Phillips C. & Bowersox S.S. (2000). Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain 84: 151-158.
36. Wang Y.-X., Gao D., Pettus M., Phillips C. & Bowersox S.S. (2000). Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats. Pain 84: 271-281.
37. Wang Y.-X. & Bowersox S.S. (2000). Analgesic properties of ziconotide, a selective blocker of N-type neuronal calcium channels. CNS Drug Reviews 6: 1-20.

在研项目：
目前主持国家自然科学基金、上海市科委以及企业合作研究多项
课题组主要研究方向：
1. 药物代谢动力学
2. 疼痛药理学
3. 心血管药理学
4. 肿瘤药理学

原文摘要：

Spinal D-Amino Acid Oxidase Contributes to Neuropathic Pain in Rats
Wen-Juan Zhao1, Zhen-Yu Gao1, Hong Wei2, Hui-Zhen Nie2, Qian Zhao2, Xiang-Jun Zhou2 and Yong-Xiang Wang2,*
1 School of Pharmacy, Shanghai Jiao Tong University,; 2 School of Pharmacy, Shanghai Jiao Tong University

Abstract

D-amino acid oxidase (DAO) is an enzyme catalyzing oxidative deamination of neutral and polar D-amino acids and expressed in the kidneys, liver and central nervous system (CNS) including the spinal cord. We have previously demonstrated that DAO gene deletion/mutation by using mutant ddY/DAO-/- mice and systemic administration of the DAO inhibitor sodium benzoate blocked formalin-induced hyperalgesia in mice. In this study, we further investigated the potential role of DAO in neuropathic pain in a rat model of tight L5/L6 spinal nerve ligation. Following L5/L6 spinal nerve ligation, the messager RNA expression (measured by real-time quantitative PCR) and enzyme activity (measured by a colorimetric method) of DAO in the lumbar spinal cord were markedly increased, in agreement with the development of neuropathic pain (mechanical allodynia). Intraperitoneal injection of sodium benzoate (400 mg/kg) specifically blocked mechanical allodynia in neuropathic rats and formalin-induced hyperalgesia but did not suppress acute pain responses in the tail flick test or formalin test. Systemic injection of sodium benzoate also inhibited DAO activity in the lumbar spinal cord of rats. Furthermore, directly intrathecal (spinal cord) injection of benzoate (30 µg/rat) specifically blocked spinal nerve ligation-induced mechanical allodynia in neuropathic rats and formalin-induced hyperalgesia (but not acute pain) in the formalin test. Based on the above results, we conclude that spinal DAO plays a pro-nociceptive (rather than anti-nociceptive) role and might be a target molecule for the treatment of chronic pain of neuropathic origin.