Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries

Ye, Yilu; Shi, Wenzhen; Zhang, Weiping; Wang, Mengling; Zhou, Yu; Fang, San‐Hua; Liu, Liying; Zhang, Qi; Yu, Yue-Ping; Wei, Er-Qing

doi:10.1016/j.ejphar.2006.11.003

Cited by 33 publications

(24 citation statements)

References 47 publications

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“…4B). Our results are consistent with the reported findings that long-term treatment with cilostazol increased angiogenesis, which can increase CBF and improve brain tissue recovery (Ye et al, 2007). Therefore, an additional use of cilostazol could improve brain tissue recovery and functional recovery in addition to the antioxidant action of probucol.…”

Section: Downloaded Fromsupporting

confidence: 82%

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Kim¹,

Park²,

Bae³

et al. 2011

J Pharmacol Exp Ther

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Hypercholesterolemia may increase stroke risk by accelerating atherosclerosis, narrowing the luminal diameter in cerebral vessels, and disrupting both vascular endothelial and smooth muscle function. In the present study, we investigated the beneficial effects of combinatorial therapy with probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet with or without 0.5% probucol and/or 0.2% cilostazol for 10 weeks. Probucol alone and probucol and cilostazol significantly decreased total, low-density lipoprotein, and high-density lipoprotein cholesterol, whereas cilostazol did not affect the plasma cholesterol levels in ApoE KO mice. Administration of probucol alone and cilostazol alone significantly decreased atherosclerotic lesion area in the aorta, with a significant decrease evident using combinatorial administration. Middle cerebral artery occlusion resulted in significantly larger infarct volumes in ApoE KO mice fed 10 weeks of high-fat diet compared with those in ApoE KO mice fed a regular diet. The infarct volume was reduced significantly using probucol alone or cilostazol alone and even was reduced significantly by their combinatorial administration. Consistent with a larger infarct size, the combinatorial therapy prominently improved neurological function. The combinatorial administration increased cerebral blood flow during ischemia. Expression of endothelial nitric oxide synthase and adiponectin in the cortex were decreased by high-fat diet but were elevated by combinatorial treatment. Adiponectin expression colocalized within the cerebral vascular endothelium. The data suggest that the combination of probucol and cilostazol prevents cerebrovascular damage in focal cerebral ischemic mice with hypercholesterolemia by up-regulation of endothelial nitric oxide synthase and adiponectin.

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confidence: 82%

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Kim¹,

Park²,

Bae³

et al. 2011

J Pharmacol Exp Ther

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“…Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15)(16)(17)(18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.…”

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confidence: 99%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

148

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Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) Infiltrating leukocytes such as lymphocytes are major effectors of postischemic brain inflammation (1-6). The phenotype and function of infiltrating lymphocytes are largely dictated by organspecific intrinsic factors during inflammatory responses (7-9), and such factors in the brain are unique in terms of cellular constituents, blood-brain barrier (10-12), and microenvironment (1-3, 7). As the most abundant cell type in the CNS, astrocytes constitute nearly 50% of the human brain's volume. Astrocytes contribute to the regulation of neural transmission, survival of neurons and other glia cells, and integrity of the blood-brain barrier. In the inflamed CNS, astrocytes engage in significant cross-talk with CNS-infiltrating immune cells by providing a major source of the proinflammatory cytokines and chemokines, thereby activating infiltrating lymphocytes. Evidence has shown that astrocytes can exert potent proinflammatory functions by producing factors including monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), etc., as their primary mode of action after CNS injury. In addition, astrocytes are considered as important nonprofessional antigen-presenting cells. Depending on the stage of brain pathology, astrocytes also possess antiinflammatory properties such as scar formation and restriction of inflammation by producing transforming growth factor-β (13,14). Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15-18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.IL-15 belongs to a family of cytokines using the common γ-chain as a component of their receptors (19,20). IL-15 interacts specifically with the high-affinity IL-15 receptor α (IL-15Rα) and binds to IL-2/IL-15Rβ and a common γ-chain expressed by target cells (21-23). In the periphery, monocytes and dendritic cells are the main sources of 25). IL-15 maintains homeostasis and cytotoxic activities of lymphocytes that bear its receptor [i.e., natural killer (NK) and CD8 + T cells] (19,20). Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major...

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“…Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) as described previously [34] , based on modifications of a rat model originally described…”

Section: Focal Cerebral Ischemiamentioning

confidence: 99%

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Shi

Zhao

et al. 2012

Neurosci. Bull.

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Objective Aquaporin-4 (AQP4), the main water channel protein in the brain, plays a critical role in water homeostasis and brain edema. Here, we investigated its role in the inflammatory responses after focal cerebral ischemia. MethodsIn AQP4-knockout (KO) and wild-type mice, focal cerebral ischemia was induced by 30 min of middle cerebral arterial occlusion (MCAO). Ischemic neuronal injury and cellular inflammatory responses, as well as the expression and localization of cysteinyl leukotriene CysLT 2 and CysLT 1 receptors, were determined at 24 and 72 h after MCAO.Results AQP4-KO mice showed more neuronal loss, more severe microglial activation and neutrophil infiltration, but less astrocyte proliferation in the brain after MCAO than wild-type mice. In addition, the protein levels of both CysLT 1 and CysLT 2 receptors were up-regulated in the ischemic brain, and the up-regulation was more pronounced in AQP4-KO mice. The CysLT 1 and CysLT 2 receptors were primarily localized in neurons, microglia and neutrophils; those localized in microglia and neutrophils were enhanced in AQP4-KO mice. Conclusion AQP4 may play an inhibitory role in postischemic inflammation.

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Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries

Cited by 33 publications

References 47 publications

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

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