磷酸二酯酶3:药物开发的新靶点

摘要/Abstract

摘要： 磷酸二酯酶(phosphodiesterase,PDE)是水解环磷酸腺苷(3',5'-cyclic adenosine monophosphate,cAMP)和环磷酸鸟苷(3',5'-cyclic guanosine monophosphate,cGMP)重要的酶。其中,PDE3由2个基因组成,在体内广泛分布,其抑制剂在抗血小板聚集、扩张血管上起重要作用。研究显示,PDE3抑制剂具有神经保护作用,为寻找防治脑缺血的药物开辟了新的途径。

关键词: 磷酸二酯酶, 神经保护, 脑缺血

Abstract: Phosphodiesterase (PDE) is hydrolase of 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP). PDE3 are composed of two genes and distributed widely in vivo.Its inhibitors have been applied in antiplatelet aggregation and vasodilation.It has been reported that PDE3 inhibitors have neuroprotective effects on cerebral ischemia, which may provide new methods to prevention and therapy of cerebral ischemia.

Key words: phosphodiesterase (PDE), neuroprotection, cerebral ischemia

中图分类号:

叶夷露, 张琦, 俞月萍. 磷酸二酯酶3:药物开发的新靶点[J]. 中国临床药理学与治疗学, 2008, 13(6): 711-715.

YE Yi-lu, ZHANG Qi, YU Yue-ping. Phosphodiesterase 3: new targets for drug development[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(6): 711-715.

参考文献

[1] Cheng CY, Boettcher B. Partial characterization of human spermatozoal phosphodiesterase and adenylate cyclase and the effect of steroids on their activities[J]. Int J Androl, 1982, 5(3): 253-266.
[2] Kuthe A, Wiedenroth A, Magert HJ, et al. Expression of different phosphodiesterase genes in human cavernous smooth muscle[J]. J Urol, 2001, 165(1): 280-283.
[3] Menniti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS:targets for drug development[J]. Nat Rev Drug Discov, 2006, 5(8): 660-670.
[4] Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms [J]. Physiol Rev, 1995, 75(4): 725-748.
[5] Essayan DM. Cyclic nucleotide phosphodiesterases[J]. J Allergy Clin Immunol, 2001, 108(5): 671-680.
[6] Conti M, Richter W, Mehats C, et al. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling[J]. J Biol Chem, 2003, 278(8): 5493-5496.
[7] Thompson WJ, Appleman MM. Characterization of cyclic nucleotide phosphodiesterases of rat tissues[J]. J Biol Chem, 1971, 246(10): 3145-3150.
[8] Wechsler J, Choi YH, Krall J, et al. Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes [J]. J Biol Chem, 2002, 277(41): 38072-38078.
[9] He R, Komas N, Ekholm D, et al. Expression and characterization of deletion recombinants of two cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE-3) [J]. Cell Biochem Biophys, 1998, 29(1/2): 89-111.
[10] Reinhardt RR, Chin E, Zhou J, et al. Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases [J]. J Clin Invest, 1995, 95(4): 1528-1538.
[11] Kitamura T, Kitamura Y, Kuroda S, et al. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt [J]. Mol Cell Biol, 1999, 19(9): 6286-6296.
[12] Masciarelli S, Horner K, Liu C, et al. Cy clic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility[J]. J Clin Invest, 2004, 114(2): 196-205.
[13] Harndahl L, Wierup N, Enerback S, et al. Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology[J]. J Biol Chem, 2004, 279(15): 15214-15222.
[14] Essayan DM. Cy clic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation[J]. Biochem Pharmacol, 1999, 57(9): 965-973.
[15] Lugnier C, Muller B, Le Bec A, et al. Characterization of indolidan-and rolipram-sensitive cyclic nucleotide phosphodiesterases in canine and human cardiac microsomal fractions[J]. J Pharmacol Exp Ther, 1993, 265(3): 1142-1151.
[16] Brunkhorst D, v der Leyen H, Meyer W, et al. Relation of positive inotropic and chronotropic effects of pimobendan, UD-CG 212 Cl, milrinone and other phosphodiesterase inhibitors to phosphodiesterase III inhibition in guinea-pig heart[J]. Naunyn Schmiedebergs Arch Pharmacol, 1989, 339(5): 575-583.
[17] Jacoby D, Mohler ER 3rd. Drug treatment of intermittent claudication[J]. Drugs, 2004, 64(15): 1657-1670.
[18] Belayev L, Busto R, Ikeda M, et al. Protection against blood-brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022:a quantitative study[J]. Brain Res, 1998, 787(2): 277-285.
[19] Turcani P, TureaniM. Effect of propentofylline on cerebral blood flow in a gerbil focal cerebral ischemia[J]. J Neurol Sci, 2001, 183(1): 57-60.
[20] JohnsonMP, McCarty DR, Chmielewski PA. Temporal dependent neuroprotection with propentofylline (HWA 285) in a temporary focal ischemia model[J]. Eur J Pharmacol, 1998, 346(2/3): 151-157.
[21] Kato H, Araki T, Itoyama Y, et al. Rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, reduces neuronal damage following cerebral ischemia in the gerbil[J]. Eur J Pharmacol, 1995, 272(1): 107-110.
[22] Nagakura A, Niimura M, Takeo S. Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cy clic AMP signal transduction system in rats[J]. Br J Pharmacol, 2002, 135(7): 1783-1793.
[23] Choi JM, Shin HK, Kim KY, et al. Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats[J]. J Pharmacol Exp Ther, 2002, 300(3): 787-793.
[24] Lee JH, Lee YK, Ishikawa M, et al. Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats--anMRI study[J]. Brain Res, 2003, 994(1): 91-98.
[25] Lee JH, Park SY, Shin YW, et al. Neuroprotection by cilostazol, a phosphodiesterase type 3 inhibitor, against apoptotic white matter changes in rat after chronic cerebral hypoperfusion[J]. Brain Res, 2006, 1082(1): 182-191.
[26] Tanaka K, Gotoh F, Fukuuchi Y, et al. Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia [J]. Stroke, 1989, 20(5): 668-673.
[27] Honda F, Imai H, Ishikawa M, et al. Cilostazol attenuates gray and white matter damage in a rodent model of focal cerebral ischemia[J]. Stroke, 2006, 37(1): 223-228.
[28] Kim KY, Shin HK, Lee JH, et al. Cilostazol enhances casein kinase 2 phosphorylation and suppresses tumor necrosis factor-alpha-induced increased phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and apoptotic cell death in SK-N-SH cells[J]. J Pharmacol Exp Ther, 2004, 308(1): 97-104.
[29] Takei K, Tokuyama K, Kato M, et al. Role of cy clic adenosine monophosphate in reducing superoxide anion generation in guinea pig alveolar macrophages[J]. Pharmacology, 1998, 57(1): 1-7.
[30] Hong KW, Kim KY, Shin HK, et al. Cilostazol prevents tumor necrosis factor-alpha-induced cell death by suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and activation of Akt cyclic AMP response element-binding protein phosphorylation [J]. J Pharmacol Exp Ther, 2003, 306(3): 1182-1190.
[31] Ronnett GV, Hester LD, Nye JS, et al. Human cortical neuronal cell line: establishment from a patient with unilateral megalencephaly[J]. Science, 1990, 248(4955): 603-605.
[32] Ye YL, Shi WZ, Zhang WP, et al. Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries[J]. Eur J Pharmacol, 2007, 557(1): 23-31.