Abstract
Cilostazol, a type-3 phosphodiesterase (PDE3) inhibitor, has become widely used as an antiplatelet drug worldwide. A recent second Cilostazol Stroke Prevention Study demonstrated that cilostazol is superior to aspirin for prevention of stroke after an ischemic stroke. However, its precise mechanisms of action remain to be determined. Here, we report that cilostazol, but not the PDE3 inhibitors cilostamide and milrinone, significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, specific inhibitors for the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP3) receptors and several common signaling pathways (PLC-γ, PI3K, Akt, p38 MAPK, and c-Jun N-terminal kinase (JNK), and the Ras/Raf/ERK/MAPK) significantly blocked the potentiation of NGF-induced neurite outgrowth by cilostazol. Using a proteomics analysis, we identified that levels of eukaryotic translation elongation factor eEF1A1 protein were significantly increased by treatment with cilostazol, but not cilostamide, in PC12 cells. Moreover, the potentiating effects of cilostazol on NGF-induced neurite outgrowth were significantly antagonized by treatment with eEF1A1 RNAi, but not the negative control of eEF1A1. These findings suggest that eEF1A1 and several common cellular signaling pathways might play a role in the mechanism of cilostazol-induced neurite outgrowth. Therefore, agents that can increase the eEF1A1 protein may have therapeutic relevance in diverse conditions with altered neurite outgrowth.
Highlights
Cilostazol, a potent inhibitor of phosphodiesterase type-3 (PDE3), is an antiplatelet/ antithrombotic agent used worldwide for the treatment of chronic arterial occlusion and intermittent claudication with peripheral occlusion and used in Japan and some other Asian countries for the prevention of ischemic stroke [1,2,3,4]
We examined the effects of the specific inhibitors of PLC-c, PI3K, Akt, p38 MAPK, and c-Jun N-terminal kinase (JNK), since these signaling molecules are activated upon the addition of nerve growth factor (NGF) [20,21,22,23,25,26,27]
The major findings of this study are that an increase in the eEF1A1 protein by cilostazol might be involved in the mechanisms of potentiation of NGF-induced neurite outgrowth by cilostazol
Summary
Cilostazol, a potent inhibitor of phosphodiesterase type-3 (PDE3), is an antiplatelet/ antithrombotic agent used worldwide for the treatment of chronic arterial occlusion and intermittent claudication with peripheral occlusion and used in Japan and some other Asian countries for the prevention of ischemic stroke [1,2,3,4]. A randomized, double-blind study of cilostazol and aspirin demonstrated that cilostazol might be more effective and safe than aspirin for Chinese patients with ischemic stroke [9,10]. The second Cilostazol Stroke Prevention Study demonstrated that cilostazol might be superior to aspirin for prevention of stroke after an ischemic stroke [12]. Taken together, these findings suggest that inhibition of PDE3 by cilostazol may contribute to its beneficial effects in these diseases the precise mechanisms underlying the beneficial effects of cilostazol are not fully understood
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