磷酸二酯酶-4：酒精依赖治疗的潜在药物靶点

神经药理学报 ›› 2013, Vol. 3 ›› Issue (1): 23-27.

磷酸二酯酶-4：酒精依赖治疗的潜在药物靶点

文睿婷¹ ，张汉霆² ，梁建辉³

1. 北京大学人民医院药剂科，北京，100044，中国
2. 美国西弗吉尼亚大学医学院，摩根顿， 26506，美国

3. 北京大学中国药物依赖性研究所，北京，100191，中国

出版日期:2013-02-26 发布日期:2014-06-27
通讯作者: 梁建辉，男，博士，研究员，博士生导师；研究方向：神经精神药理学；Tel：+86-010-82802452，Fax：+86-010-62032624，E-mail：liangjh@bjmu.edu.cn
作者简介:文睿婷，女，博士，主管药师；研究方向：神经精神药理学，临床药学
基金资助:
国家重点基础研究发展计划（973 计划）(No.2009CB522003)；国家自然科学基金（No.30870894）；“十二五”国家科技支撑计划资助项目（No.2011BAK04B08）；公安部重点研究计划（No.2009ZDYJHLJT003）

Phosphodiesterase-4 (PDE4)：the Potential Therapeutic Target for Alcohol Dependence

WEN Rui-ting¹ ZHANG Han-ting² LIANG Jian-hui³

1. Pharmacy Department of Peking University People’s Hospital, Beijing, 100044, China
2. West Virginia University Health Sciences Center，Morgantown，WV 26506, USA

3. National Institute on Drug Dependence, Beijing, 100191, China

Online:2013-02-26 Published:2014-06-27
Contact: 梁建辉，男，博士，研究员，博士生导师；研究方向：神经精神药理学；Tel：+86-010-82802452，Fax：+86-010-62032624，E-mail：liangjh@bjmu.edu.cn
About author:文睿婷，女，博士，主管药师；研究方向：神经精神药理学，临床药学
Supported by:
国家重点基础研究发展计划（973 计划）(No.2009CB522003)；国家自然科学基金（No.30870894）；“十二五”国家科技支撑计划资助项目（No.2011BAK04B08）；公安部重点研究计划（No.2009ZDYJHLJT003）

摘要/Abstract

摘要： 酒精依赖作为一种神经精神疾病，已成为公共健康和社会安全的严重隐患。近年来神经分子生物学研究显示，细胞内环腺苷酸（cyclic adenosine monophosphate, cAMP）信号转导通路的功能在酒精依赖的形成和发展过程中发挥重要的调节作用。磷酸二酯酶-4（phosphodiesterase-4, PDE4）作为PDE超家族的一员，对细胞内cAMP浓度及其下行信号转导具有选择性和关键性的调控作用，一系列研究显示其可能是酒精依赖的新型药物治疗靶点。PDE4抑制剂的研发技术不断成熟，为其临床应用的拓展奠定了良好基础。基于PDE4及其抑制剂的深入研究，对新型酒精依赖治疗药物的开发具有重要意义。本文结合国内外最新研究进展，就PDE4作为药物靶点应用于酒精依赖治疗的可行性依据作一简要综述。

关键词: 酒精依赖, 细胞内环腺苷酸, 磷酸二酯酶-4, 磷酸二酯酶-4抑制剂

Abstract: Alcohol dependence is a psychiatric disease, which leads to serious individual and social harms. Latest advances in neurobiological research indicate the important role of cyclic adenosine monophosphate (cAMP) signal transduction in the development of alcohol drinking behavior. As a member of the phosphodiesterase (PDE) super family, PDE4 specifically catalyzes the hydrolysis of cAMP and represents a key point in regulating intracellular cAMP levels. Accumulating studies show that PDE4 inhibitors may be a novel class of pharmacotherapies for alcohol dependence. Here we review the existing evidence that support PDE4 as a novel theraputic target for alcohol dependence.

Key words: alcohol dependence, cyclic adenosine monophosphate (cAMP), phosphodiesterase-4 (PDE4), PDE4 inhibitor

文睿婷，张汉霆，梁建辉. 磷酸二酯酶-4：酒精依赖治疗的潜在药物靶点[J]. 神经药理学报, 2013, 3(1): 23-27.

WEN Rui-ting ZHANG Han-ting LIANG Jian-hui. Phosphodiesterase-4 (PDE4)：the Potential Therapeutic Target for Alcohol Dependence[J]. Acta Neuropharmacologica, 2013, 3(1): 23-27.

参考文献

[1] World Health Organization. Global status report on alcohol and health[M]. Geneva, Switzerland: World Health Organization, 2011: 286.

[2] 高丽波,钟树荣,包建军,等. 酒精依赖治疗的研究进展[J]. 医学研究杂志, 2010, 39(8): 107-110.

[3] 梁建辉, 刘青. 酒精成瘾治疗药物药理活性筛选和药效学评价技术平台的研究[J]. 山西大同大学学报（自然科学版）, 2009, 25(1):45-47.

[4] David W Oslin, Wade H Berrettini, Charles P O’Brien. Targeting treatments for alcohol dependence: the pharmacogenetics of naltrexone[J]. Addict Biol, 2006, 11(3-4):397–403.

[5] Subhash C Pandey. The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction[J]. Pharmacol Ther, 2004, 104(1): 47-58.

[6] George F Koob. Alcoholism: allostasis and beyond[J]. Alcohol Clin Exp Res, 2003, 27(2):232– 243.

[7] George F Koob. Neuroadaptive mechanisms of addiction: studies on the extended amygdala[J]. Eur Neuropsychopharmacol, 2003, 13(6):442– 452.

[8] Rueben A Gonzales, Martin O Job, William M Doyon. The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement[J]. Pharmacol Ther, 2004, 103(2):121–146.

[9] Subhash C Pandey, Navdha Mittal, Lawrence Lumeng, et al. Involvement of the cyclic AMP responsive element binding protein gene transcription factor in genetic preference for alcohol drinking behavior[J]. Alcohol Clin Exp Res, 1999, 23(9):1425-1434.

[10] Subhash C Pandey, Zhang Huai-bo, Adip Roy, et al. Deficits in amygdaloid cAMP responsive element binding protein signaling play a role in genetic predisposition to anxiety and alcoholism[J]. J Clin Invest, 2005, 115(10):2762-2773.

[11] Kevin P Conway, Wilson Compton, Frederick S Stinson, et al. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions[J]. J Clin Psychiatry, 2006, 67(2):247–257.

[12] 张振华, 邱毅, 赵振国, 等. 酒精成瘾的受体后信号转导[J]. 生理科学进展, 2008, 39(4): 319-324.

[13] Subhash C Pandey, Toshikazu Saito, M Yoshimura, et al. cAMP signaling cascade:a promising role in ethanol tolerance and dependence[J]. Alcohol Clin Exp Res, 2001, 25(2):46S-48S.

[14] Kaushik Misra, Subhash C Pandey. Differences in basal levels of CREB and NPY in nucleus accumbens regions between C57BL/6 and DBA/2 mice differing in inborn alcohol drinking behavior[J]. J Neurosci Res, 2003, 74(6):967-975.

[15] Subhash C Pandey, Adip Roy, Zhang Huai-bo, et al. Partial deletion of the cAMP response element binding protein gene promotes alcohol drinking behaviors[J]. J Neurosci, 2004, 24(21):5022–5030.

[16] Subhash C Pandey, Adip Roy, Zhang Huai-bo. The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats[J]. Alcohol Clin Exp Res, 2003, 27(3):396-409.

[17] Andrew T Bender, Joseph A Beavo. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use[J]. Pharmacol Rev, 2006, 58(3):488–520.

[18] Zhang Han-ting. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs[J]. Curr Pharm Des, 2009, 15(14):1688-1698.

[19] S Perez-Torres, X Miro, J M Palacios, et al. Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and [3H]rolipram binding autoradiography: Comparison with monkey and rat brain[J]. J Chem Neuroanat, 2000, 20(3-4): 349–374.

[20] Zhang Han-ting, Huang Ying, S-L Catherine Jin, et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme[J]. Neuropsychopharmacology, 2002, 27(4): 587-595.

[21] Li Yun-feng, Cheng Yu-fang, Huang Ying, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling[J]. J Neurosci, 2011, 31(1):172–183.

[22] Hu Wei, Tina Lu, Alan Chen, et al. Inhibition of phosphodiesterase-4 decreases ethanol intake in mice[J]. Psychopharmacology, 2011, 218(2):331-339.

[23] Wen Rui-ting, Zhang Min, Qin Wang-jun, et al. The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring fawn-hooded rats[J]. Alcohol Clin Exp Res, 2012, 36(12):2157-2167.

[24] Richard L Bell, Marcelo F Lopez, Cui Chang-hai, et al. Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence [J]. Addict Biol, 2013, doi: 10.1111/adb.12106.

[25] Mark A Giembycz, Stephen K Field. Roflumilast: first phosphodiesterase-4 inhibitor approved for treatment of COPD[J]. Drug Des Devel Ther, 2010, 21(4): 147-158.

[26] Altana Roflumilast-APTA 2217, B9302-107, BY 217, BYK20869[J]. Drugs R D, 2004, 5(3): 176-181.

[27] 李灵君, 韩尚河, 陈国良. 磷酸二酯酶-4抑制剂的研究进展[J]. 沈阳药科大学学报, 2013, 30(7):568-576.

[28] Rajarshi Sengupta, Sun Tao, Nicole M Warrington, et al. Treating brain tumors with PDE4 inhibitors[J]. Trends Pharmacol Sci, 2011, 32(6):337-344.