Protective effects of cilostazol against transient focal cerebral ischemia and chronic cerebral hypoperfusion injury

CNS Neuroscience and Therapeutics

Volumn 14, Issue 2, 2008, Pages 143-152

  Lee, Jeong Hyun ^a   Park, So Youn ^a   Shin, Hwa Kyoung ^a,b   Kim, Chi Dae ^a,b   Lee, Won Suk ^a,b   Hong, Ki Whan ^b  

^a Pusan National University School of Medicine   (South Korea)

^b Pusan National University   (South Korea)

Author keywords

Anti inflammatory drugs; Antioxidants; Apoptosis; Brain ischemia; Cilostazol; K+ channels; Neuroprotective drugs

Indexed keywords

3 (4 TERT BUTYLPHENYLSULFONYL) 2 PROPENENITRILE; 3 (5 CHLORO 2 METHOXYPHENYL) 3 FLUORO 2,3 DIHYDRO 6 TRIFLUOROMETHYL 1H INDOL 2 ONE; 3,4 DIHYDRO 6 [4 [1 (4 HYDROXYCYCLOHEXYL) 1H TETRAZOL 5 YL]BUTOXY] 2(1H) QUINOLINONE; ACETYLSALICYLIC ACID; CILOSTAZOL; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; DEHYDROCILOSTAZOL; DIPYRIDAMOLE; KT 5720; KT 5823; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PHOSPHODIESTERASE III; PLACEBO; POTASSIUM CHANNEL;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ASTROCYTE; BRAIN EDEMA; BRAIN INFARCTION; BRAIN INJURY; BRAIN ISCHEMIA; BRAIN PERFUSION; BRAIN PROTECTION; CELL VACUOLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; HUMAN; INTERMITTENT CLAUDICATION; MICROGLIA; MULTICENTER STUDY; NUCLEAR MAGNETIC RESONANCE IMAGING; RANDOMIZED CONTROLLED TRIAL; REVIEW; THROMBOCYTE AGGREGATION INHIBITION; VASODILATATION; WHITE MATTER;

CEREBROVASCULAR DISORDERS; CHRONIC DISEASE; CLINICAL TRIALS AS TOPIC; HUMANS; ISCHEMIC ATTACK, TRANSIENT; NEUROPROTECTIVE AGENTS; STROKE; TETRAZOLES;

EID: 44049106204     PISSN: 17555930     EISSN: 17555949     Source Type: Journal    
DOI: 10.1111/j.1527-3458.2008.00042.x     Document Type: Review

References (80)

1. Aizawa T, Wei H, Miano JM, Abe J, Berk BC, Yan C (2003) Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res 93 : 406 413.
2. Akiguchi I, Tomimoto H, Suenaga T, Wakita H, Budka H (1997) Alterations in glia and axons in the brains of Binswanger's disease patients. Stroke 28 : 1423 1429.
3. Akiyama H, Kudo S, Shimizu T (1985) The absorption, distribution and excretion of a new antithrombotic and vasodilating agent, cilostazol, in rat, rabbit, dog and man. Arzneimittelforschung 35 : 1124 1132.
4. Bednar MM (2000) Stroke: Antithrombin versus anti-platelet therapy. Expert Opin Investig Drugs 9 : 355 369.
5. Betz AL (1996) Alterations in cerebral endothelial cell function in ischemia. Adv Neurol 71 : 301 311.
6. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286 : 1358 1362.
7. Boone KB, Miller BL, Lesser IM, Mehringer CM, Hill-Gutierrez E, Goldberg MA, Berman NG (1992) Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect. Arch Neurol 49 : 549 554.
8. Bramer SL, Forbes WP, Mallikaarjun S (1999) Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease. Clin Pharmacokinet 37 (Suppl. 2 1 11.
9. Bredesen DE (1995) Neural apoptosis. Ann Neurol 38 : 839 851.
10. Chan PH (2005) Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke. Ann N Y Acad Sci 1042 : 203 209.
11. Cheney JA, Weisser JD, Bareyre FM, Laurer HL, Saatman KE, Raghupathi R, Gribkoff V, Starrett JE Jr., McIntosh TK (2001) The maxi-K channel opener BMS-204352 attenuates regional cerebral edema and neurologic motor impairment after experimental brain injury. J Cereb Blood Flow Metab 21 : 396 403.
12. Cho KO, La HO, Cho YJ, Sung KW, Kim SY (2006) Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res 83 : 285 291.
13. Choi JM, Shin HK, Kim KY, Lee JH, Hong KW (2002) Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats. J Pharmacol Exp Ther 300 : 787 793.
14. Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr. 1998) Cilostazol has beneficial effects in treatment of intermittent claudication: Results from a multicenter, randomized, prospective, double-blind trial. Circulation 98 : 678 686.
15. de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, LeMeur M, et al. 1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94 : 7303 7730.
16. Douglas JS Jr., Holmes DR Jr., Kereiakes DJ, Grines CL, Block E, Ghazzal ZM, Morris DC, Liberman H, Parker K, Jurkovitz C, et al. 2005) Coronary stent restenosis in patients treated with cilostazol. Circulation 112 : 2826 2832.
17. Ducrocq S, Benjelloun N, Plotkine M, Ben-Ari Y, Charriaut-Marlangue C (2000) Poly(ADP-ribose) synthase inhibition reduces ischemic injury and inflammation in neonatal rat brain. J Neurochem 74 : 2504 2511.
18. Easton JD (1998) What have we learned from recent antiplatelet trials? Neurology 51 : S36 S38.
19. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, et al. 1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3 : 1089 1095.
20. Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated by the activation of poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 17 : 1143 1151.
21. Finkbeiner S (2000) CREB couples neurotrophin signals to survival messages. Neuron 25 : 11 14.
22. Franke B, Bayatti N, and Engele J (2000) Neurotrophins require distinct extracellular signals to promote the survival of CNS neurons in vitro. Exp Neurol 165 : 125 135.
23. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59 : 675 680.
24. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, Shinohara Y, Itoh E, Matsuda T, Sawada T, et al. 2000) Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis 9 : 147 157.
25. Gregersen R, Lambertsen K, Finsen B (2000) Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 20 : 53 65.
26. Gribkoff VK, Starrett JE Jr., Dworetzky SI, Hewawasam P, Boissard CG, Cook DA, Frantz SW, Heman K, Hibbard JR, Huston K, et al. 2001) Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat Med 7 : 471 477.
27. Hoehn-Berlage M, Norris DG, Kohno K, Mies G, Leibfritz D, Hossmann KA (1995) Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab 15 : 1002 1011.
28. Hollensworth SB, Shen C, Sim JE, Spitz DR, Wilsonn GL, LeDoux SP (2000) Glial cell type-specific responses to menadione-induced oxidative stress. Free Radic Biol Med 28 : 1161 1174.
29. Honda F, Imai H, Ishikawa M, Kubota C, Shimizu T, Fukunaga M, Saito N (2006) Cilostazol attenuates gray and white matter damage in a rodent model of focal cerebral ischemia. Stroke 37 : 223 228.
30. Hong KW, Kim KY, Shin HK, Lee JH, Choi JM, Kwak YG, Kim CD, Lee WS, Rhim BY (2003) 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 Pharmacol Exp Ther 306 : 1182 1190.
31. Hong SJ, Dawson TM, Dawson VL (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci 25 : 259 264.
32. Huang YN (2007) Cilostazol reduces cerebral hemorrhage in secondary stroke prevention: A multicenter, randomized, double-blinded, aspirin control study. 16th Annual European Stroke Conference, Glasgow, UK.
33. Ihara M, Tomimoto H, Kinoshita M, Oh J, Noda M, Wakita H, Akiguchi I, Shibasaki H (2001) Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J Cereb Blood Flow Metab 21 : 828 834.
34. Inoue T, Kobayashi M, Uetsuka Y, Uchiyama S (2006) Pharmacoeconomic analysis of cilostazol for the secondary prevention of cerebral infarction. Circ J 70 : 453 458.
35. Kambayashi J, Liu Y, Sun B, Shakur Y, Yoshitake M, Czerwiec F (2003) Cilostazol as a unique antithrombotic agent. Curr Pharm Des 9 : 2289 2302.
36. Kim KY, Shin HK, Choi JM, Hong KW (2002) Inhibition of lipopolysaccharide-induced apoptosis by cilostazol in human umbilical vein endothelial cells. J Pharmacol Exp Ther 300 : 709 715.
37. Kim KY, Shin HK, Lee JH, Kim CD, Lee WS, Rhim BY, Shin YW, Hong KW (2004) 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 Pharmacol Exp Ther 308 : 97 104.
38. Kimura Y, Tani T, Kanbe T, Watanabe K (1985) Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung 35 : 1144 1149.
39. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275 : 1132 1136.
40. Kohda N, Tani T, Nakayama S, Adachi T, Marukawa K, Ito R, Ishida K, Matsumoto Y, Kimura Y (1999) Effect of cilostazol, a phosphodiesterase III inhibitor, on experimental thrombosis in the porcine carotid artery. Thromb Res 96 : 261 268.
41. Komjati K, Mabley JG, Virag L, Southan GJ, Salzman AL, Szabo C (2004) Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. Int J Mol Med 13 : 373 382.
42. Kurumatani T, Kudo T, Ikura Y, Takeda M (1998) White matter changes in the gerbil brain under chronic cerebral hypoperfusion. Stroke 29 : 1058 1062.
43. Latorre R, Oberhauser A, Labarca P, Alvarez O (1989) Varieties of calcium-activated potassium channels. Annu Rev Physiol 51 : 385 399.
44. Lawrence MS, McLaughlin JR, Sun GH, Ho DY, McIntosh L, Kunis DM, Sapolsky RM, Steinberg GK (1997) Herpes simplex viral vectors expressing Bcl-2 are neuroprotective when delivered after a stroke. J Cereb Blood Flow Metab 17 : 740 744.
45. Lawson K (2000) Potassium channel openers as potential therapeutic weapons in ion channel disease. Kidney Int 57 : 838 845.
46. Lee JH, Lee YK, Ishikawa M, Koga K, Fukunaga M, Miyakoda G, Mori T, Hosokawa T, Hong KW (2003) Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats-an MRI study. Brain Res 994 : 91 98.
47. Lee JH, Kim KY, Lee YK, Park SY, Kim CD, Lee WS, Rhim BY, Hong KW (2004) Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats. J Pharmacol Exp Ther 308 : 896 903.
48. Lee JH, Oh GT, Park SY, Choi JH, Park JG, Kim CD, Lee WS, Rhim BY, Shin YW, Hong KW (2005) Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-alpha formation in low-density lipoprotein receptor-null mice fed high cholesterol. J Pharmacol Exp Ther 313 : 502 509.
49. Lee JH, Park SY, Shin YW, Hong KW, Kim CD, Sung SM, Kim KY, Lee WS (2006) Neuroprotection by cilostazol, a phosphodiesterase type 3 inhibitor, against apoptotic white matter changes in rat after chronic cerebral hypoperfusion. Brain Res 1082 : 182 191.
50. Lee JH, Park SY, Shin HK, Kim CD, Lee WS, Hong KW (2007) Poly(ADP-ribose) polymerase inhibition by cilostazol is implicated in the neuroprotective effect against focal cerebral ischemic infarct in rat. Brain Res 1152 : 182 190.
51. Majid A, Delanty N, Kantor J (2001) Antiplatelet agents for secondary prevention of ischemic stroke. Ann Pharmacother 35 : 1241 1247.
52. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C, et al. 1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13 : 1017 1030.
53. Matsumoto Y, Marukawa K, Okumura H, Adachi T, Tani T, Kimura Y (1999) Comparative study of antiplatelet drugs in vitro: Distinct effects of cAMP-elevating drugs and GPIIb/IIIa antagonists on thrombin-induced platelet responses. Thromb Res 95 : 19 29.
54. Minami N, Suzuki Y, Yamamoto M, Kihira H, Imai E, Wada H, Kimura Y, Ikeda Y, Shiku H, Nishikawa M (1997) Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci 61 : 383 389.
55. Ollivier V, Parry GCN, Cobb RR, de Prost D, Mackman N (1996) Elevated cyclic AMP inhibits NF-κB-mediated transcription in human monocytic cells and endothelial cells. J Biol Chem 271 : 20828 20835.
56. Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27 : 1641 1646.
57. Park SY, Lee JH, Kim YK, Kim CD, Rhim BY, Lee WS, Hong KW (2005) Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation. J Pharmacol Exp Ther 312 : 1241 1248.
58. Park SY, Lee JH, Kim CD, Lee WS, Park WS, Han J, Kwak YG, Kim KY, Hong KW (2006) Cilostazol suppresses superoxide production and expression of adhesion molecules in human endothelial cells via mediation of cAMP-dependent protein kinase-mediated maxi-K channel activation. J Pharmacol Exp Ther 317 : 1238 1245.
59. Petito CK, Olarte JP, Roberts B, Nowak TS Jr., Pulsinelli WA (1998) Selective glial vulnerability following transient global ischemia in rat brain. J Neuropathol Exp Neurol 57 : 231 238.
60. Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24 : 458 466.
61. Robitaille R, Charlton MP (1992) Presynaptic calcium signals and transmitter release are modulated by calcium-activated potassium channels. J Neurosci 12 : 297 305.
62. Sage JI, Van Uitert RL, Duffy TE (1984) Early changes in blood brain barrier permeability to small molecules after transient cerebral ischemia. Stroke 15 : 46 50.
63. Sawada M, Kondo N, Suzumura A, Marunouchi T (1989) Production of tumor necrosis factor-α by microglia and astrocytes in culture. Brain Res 491 : 394 397.
64. Shakur Y, Fong M, Hensley J, Cone J, Movsesian MA, Kambayashi J, Yoshitake M, Liu Y (2002) Comparison of the effects of cilostazol and milrinone on cAMP-PDE activity, intracellular cAMP and calcium in the heart. Cardiovasc Drugs Ther 16 : 417 427.
65. Shin HK, Kim YK, Kim KY, Lee JH, Hong KW (2004) Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein receptor-1 activation: Prevention by cilostazol. Circulation 109 : 1022 1028.
66. Shinoda-Tagawa T, Yamasaki Y, Yoshida S, Kajimoto Y, Tsujino T, Hakui N, Matsumoto M, Hori M (2002) A phosphodiesterase inhibitor, cilostazol, prevents the onset of silent brain infarction in Japanese subjects with Type II diabetes. Diabetologia 45 : 188 194.
67. Shinohara Y (2006) Antiplatelet cilostazol is effective in the prevention of pneumonia in ischemic stroke patients in the chronic stage. Cerebrovasc Dis 22 : 57 60.
68. Tanaka K (2001) Alteration of second messengers during acute cerebral ischemia-adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein. Prog Neurobiol 65 : 173 207.
69. Tanaka K, Ogawa N, Asanuma M, Kondo Y, Nomura M (1996) Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion. Brain Res 729 : 55 65.
70. Taupin V, Renno T, Bourbonniere L, Peterson AC, Rodriguez M, Owens T (1997) Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-α in the central nervous system. Eur J Immunol 27 : 905 913.
71. Tomimoto H, Ihara M, Wakita H, Ohtani R, Lin JX, Akiguchi I, Kinoshita M, Shibasaki H (2003) Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol 106 : 527 534.
72. Wakida K, Morimoto N, Shimazawa M, Hozumi I, Nagase H, Inuzuka T, Hara H (2006) Cilostazol reduces ischemic brain damage partly by inducing metallothionein-1 and -2. Brain Res 1116 : 187 193.
73. Wakita H, Tomimoto H, Akiguchi I, Kimura J (1994) Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: An immunohistochemical study. Acta Neuropathol 87 : 484 492.
74. Wakita H, Tomimoto H, Akiguchi I, Lin JX, Miyamoto K, Oka N (1999) A cyclooxygenase-2 inhibitor attenuates white matter damage in chronic cerebral ischemia. NeuroReport 10 : 1461 1465.
75. Walton MR, Dragunow I (2000) Is CREB a key to neuronal survival? Trends Neurosci 23 : 48 53.
76. Walton M, Woodgate AM, Muravlev A, Xu R, During MJ, Dragunow M (1999) CREB phosphorylation promotes nerve cell survival. J Neurochem 73 : 1836 1842.
77. Watanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T (2006) Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke 37 : 1539 1545.
78. Yang GY, Gong C, Qin Z, Liu XH, Lorris Betz A (1999) Tumor necrosis factor α expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice. Brain Res Mol Brain Res 69 : 135 143.
79. Ye YL, Shi WZ, Zhang WP, Wang ML, Zhou Y, Fang SH, Liu LY, Zhang Q, Yu YP, Wei EQ (2007) Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries. Eur J Pharmacol 557 : 23 31.
80. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Ted M, Dawson TM, Dawson VL (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297 : 259 264.