Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats—an MRI study

Lee, Jeong Hyun; Lee, Yong-Kyu; Ishikawa, Makoto; Koga, Keiko; Fukunaga, Mari; Miyakoda, Goro; Mori, Toyoki; Hosokawa, Tetsumi; Hong, Ki Whan

doi:10.1016/j.brainres.2003.09.021

Cited by 55 publications

(30 citation statements)

References 23 publications

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“…Its principal reported actions include inhibition of platelet aggregation (Kimura et al, 1985;Kohda et al, 1999), antithrombosis in feline cerebral ischemia, and vasodilation via an increased cAMP level (Tanaka et al, 1989). It has been reported recently that cilostazol exerts neuroprotective effect against ischemic brain injury Lee et al, 2003), and this neuroprotective potential has been ascribed to its anti-inflammatory and antiapoptotic effects mediated by scavenging hydroxyl radicals, decrease the formation of tumor necrosis factor-␣, and inhibition of poly(ADP-ribose) polymerase activity (Lee et al, 2004(Lee et al, , 2007(Lee et al, , 2008. We further reported that cilostazol provided neuroprotection against the permanent, filamental MCA occlusion-mediated increases in metallothionein-1 and -2 (Wakida et al, 2006).…”

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confidence: 99%

Combination Treatment with Normobaric Hyperoxia and Cilostazol Protects Mice against Focal Cerebral Ischemia-Induced Neuronal Damage Better Than Each Treatment Alone

Nonaka¹,

Koumura²,

Hyakkoku³

et al. 2009

J Pharmacol Exp Ther

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Normobaric hyperoxia (NBO) and cilostazol (6-[4-(1-cyclohexy-1H-tetrazol-5-yl)butoxyl]-3,4-dihydro-2-(1H)-quinolinone) (a selective inhibitor of phosphodiesterase 3) have each been reported to exert neuroprotective effects against acute brain injury after cerebral ischemia in rodents. Here, we evaluated the potential neuroprotective effects of combination treatment with NBO and cilostazol against acute and subacute brain injuries after simulated stroke. Mice subjected to 2-h filamental middle cerebral artery (MCA) occlusion were treated with NBO (95% O 2 , during the ischemia) alone, with cilostazol (3 mg/kg i.p. after the ischemia) alone, with both of these treatments (combination), or with vehicle. The histological and neurobehavioral outcomes were assessed at acute (1 day) or subacute (7 days) stages after reperfusion. We measured regional cerebral blood flow (rCBF) during and after ischemia by laser-Doppler flowmetry and recovery (versus vehicle) in the combination therapy group just after reperfusion. Mean acute and subacute lesion volumes were significantly reduced in the combination group but not in the two monotherapy groups. The combination therapy increased endothelial nitric-oxide synthase (eNOS) activity in the lesion area after ischemia versus vehicle. Combination therapy with NBO plus cilostazol protected mice subjected to focal cerebral ischemia by improvement of rCBF after reperfusion, in part in association with eNOS activity.

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confidence: 99%

Combination Treatment with Normobaric Hyperoxia and Cilostazol Protects Mice against Focal Cerebral Ischemia-Induced Neuronal Damage Better Than Each Treatment Alone

Nonaka¹,

Koumura²,

Hyakkoku³

et al. 2009

J Pharmacol Exp Ther

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“…Recently, few reports described other nonantiplatelet neuroprotective effects of cilostazol, such as anticytotoxic effect and antiapoptosis effect, in focal cerebral ischemic models. [3][4][5][6] The main mechanism of this action is increased cAMP-responsive element binding protein (CREB) phosphorylation through intracellular signaling from type III phosphodiesterase-cAMP cascade, which could induce subsequent activation of antiapoptotic cascade. 7 Although the neuroprotective mechanism of cilostazol has been investigated at an early period after ischemia, 3 to our knowledge, there is no report that describes the brain-protective effects of cilostazol on WMLs in the chronic stage after ischemic insult.…”

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confidence: 99%

Cilostazol Protects Against Brain White Matter Damage and Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion

Watanabe

Zhang

Liu

et al. 2006

Stroke

138

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Background and Purpose-White matter lesions contribute to cognitive impairment in poststroke patients. The present study was designed to assess the neuroprotective mechanisms of cilostazol, a potent inhibitor of type III phosphodiesterase, through signaling pathways that lead to activation of transcription factor cAMP-responsive element binding protein (CREB) phosphorylation using rat chronic cerebral hypoperfusion model. Methods-Rats underwent bilateral common carotid artery ligation. They were divided into the cilostazol group (nϭ80) and the vehicle (control) group (nϭ80). Performance at the Morris water maze task and immunohistochemistry for 4-hydroxy-2-nonenal (HNE), glutathione-S-transferase-pi (GST-pi), ionized calcium-binding adaptor molecule 1, phosphorylated CREB (p-CREB), Bcl-2, and cyclooxygenase-2 (COX-2) were analyzed at baseline and at 3, 7, 14, 21, and 28 days after hypoperfusion. Result-Cilostazol significantly improved spatial learning memory (6.8Ϯ2.3 seconds; PϽ0.05) at 7 days after hypoperfusion.Cilostazol markedly suppressed accumulation of HNE-modified protein and loss of GST-pi-positive oligodendrocytes in the cerebral white matter during the early period after hypoperfusion (PϽ0.05). Cilostazol upregulated p-CREB and Bcl-2 (PϽ0.05), increased COX-2 expression, and reduced microglial activation in the early period of hypoperfusion. Conclusion-Our results indicate that cilostazol exerts a brain-protective effect through the CREB phosphorylation pathway leading to upregulation of Bcl-2 and COX-2 expressions and suggest that cilostazol is potentially useful for the treatment of cognitive impairment in poststroke patients.

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“…Interestingly, Lee et al (33) reported that, in rat brains subjected to middle cerebral artery (MCA) occlusion followed by 24-h reperfusion, the cerebral infarct size was little affected by oral administration of aspirin (300 mg/kg) or clopidogrel (30 mg/kg), but it was significantly reduced by cilostazol (30 mg/kg). Thus, cilostazol has been suggested to have a neuroprotective effect against ischemic brain injury (34,35). Its neuroprotective potential has been based on the following: a) its anti-inflammatory and antiapoptotic effects (mediated by scavenging of hydroxyl radicals), b) decreased formation of tumor necrosis factor-α, and c) an inhibition of poly(ADP-ribose) polymerase activity (36 -38).…”

Section: Possible Mechanisms Of the Protective Effects Of Cilostazol mentioning

confidence: 99%

Novel Situations of Endothelial Injury in Stroke — Mechanisms of Stroke and Strategy of Drug Development: Protective Effects of Antiplatelet Agents Against Stroke

Shimazawa

Hara

2011

J Pharmacol Sci

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Abstract. Stroke is the second cause of mortality worldwide, and intravenous administration of tissue plasminogen activator (t-PA) within 3 h of symptom onset is the only treatment proven effective for re-establishment of cerebral blood flow following acute ischemic stroke. However, its widespread application remains limited by its narrow therapeutic time window and the related risks of intracranial hemorrhage. On the other hand, in patients with atherothrombotic risk, antiplatelet agents are widely used to decrease the risk of occlusive arterial events. All of these drugs are used during coronary interventions and in the medical management of acute coronary syndromes. In contrast, only aspirin, cilostazol, and thienopyridine derivatives (ticlopidine and clopidogrel) are used in the long-term prevention of cerebrovascular events in patients with risk of recurrence. In this paper, we introduce recent clinical findings on antiplatelet therapies for secondary prevention after ischemic stroke and describe basic research that has focused on cerebrovascular protection by cilostazol, which has a unique pharmacological profile.

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Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats—an MRI study

Cited by 55 publications

References 23 publications

Combination Treatment with Normobaric Hyperoxia and Cilostazol Protects Mice against Focal Cerebral Ischemia-Induced Neuronal Damage Better Than Each Treatment Alone

Combination Treatment with Normobaric Hyperoxia and Cilostazol Protects Mice against Focal Cerebral Ischemia-Induced Neuronal Damage Better Than Each Treatment Alone

Cilostazol Protects Against Brain White Matter Damage and Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion

Novel Situations of Endothelial Injury in Stroke — Mechanisms of Stroke and Strategy of Drug Development: Protective Effects of Antiplatelet Agents Against Stroke

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