Post-stroke administration of cilostazol changes metabolic profile in transsulfuration pathway of ischemic brain in a mouse model

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Cilostazol, an inhibitor of phosphodiesterase3 (PDE3), has been suggested to minimize post-stroke cognitive impairment. However, mechanisms underlining these beneficial effects remain elusive. We, therefore, examined effects of cilostazol on biochemical characteristics of cerebral metabolism using mouse cerebral ischemia model in vivo. To decipher multifold mechanisms whereby cilostazol changes metabolic dynamics in different regions of the brain, we conducted metabolome analysis to target metabolic pathways responding to the cilostazol treatment. To this end, focal ischemia was induced by a left middle cerebral artery occlusion. Right after the induction of ischemia, either the cilostazol (30 mg/kg or 100 mg/kg) or vehicle was administered orally. At 60 min after the occlusion, metabolic processes were rapidly suspended by the in situ freezing to minimize autolytic changes. Metabolites were extracted and measured with high-throughput capillary electrophoresis mass spectrometry. We then conducted cluster analysis to compare and contrast changes in 90 metabolites extracted from contralateral (CL) and ipsilateral (IL) hemispheric brains. In both CL and IL, the cilostazol treatment tended to increase cystathionine, taurine, cysteine, and the reduced form of glutathione, suggesting that the treatment alters sulfur amino acid metabolism and the transsulfuration pathway. Such an observation led us to hypothesize that cilostazol controls the activity of cystathionine β-synthase (CBS) which catalyzes the first committed step of the transsulfuration pathway. When primary cultured astrocytes which endogenously express CBS were treated with cilostazol, CBS expression increased as judged by Western blot analysis. These results indicate that cilostazol treatment could achieve neuroprotection via controlling CBS activity. Alteration of metabolites in the transsulfulation pathway induced by cilostazol oral administration may lead to beneficial therapeutic stratagem in cerebrovascular diseases.
日本微小循環学会の論文

Post-stroke administration of cilostazol changes metabolic profile in transsulfuration pathway of ischemic brain in a mouse model

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