Cilostazol was developed as a selective inhibitor of
cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and
vasodilator properties of
cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as
intermittent claudication and recurrent
stroke. In this review, the novel action mechanism (s) of
cilostazol are overviewed with the focus on the action of
cilostazol in in vitro and in vivo studies as a
maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with
cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in
cerebral infarct area was evident in rats subjected to
ischemia/reperfusion. Increase in
cyclic AMP and decrease in
TNF-alpha levels were identified in the ipsilateral cortex under treatment with
cilostazol accompanied by decreased Bax formation and
cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells.
Cilostazol suppressed
TNF-alpha-induced decrease in viability of SK-N-SH (human
neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by
iberiotoxin, a
maxi-K(+) channel blocker. Further,
cilostazol prevented
TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells.
Cilostazol increased K(+) current in SK-N-SH cells by opening the
maxi-K channels. Thus, it was suggested that the action of
cilostazol to promote cell survival was ascribed to the
maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.