Protective effects of cilostazol against transient focal cerebral ischemia and chronic cerebral hypoperfusion injury

Abstract

Cilostazol increases intracellular cyclic adenosine monophosphate (cyclic AMP) levels by inhibiting type III phosphodiesterase. It was approved by the Food and Drug Administration for the treatment of intermittent claudication. Its principal actions include inhibition of platelet aggregation, antithrombotic action in cerebral ischemia, and vasodilation, mediated by increased cyclic AMP levels. In a multicenter, randomized, placebo-controlled, double-blind clinical trial, cilostazol has been shown to protect patients from recurrent cerebral infarction. It has been recently suggested that cilastozol could be useful in the treatment of transient focal cerebral ischemic injury. Beneficial effects of cilostazol in cerebral ischemic infarction and edema formation has been confirmed in rats by the magnetic resonance imaging (MRI). The preventive effect was ascribed to cAMP-dependent protein kinase (PKA)-coupled maxi-K channel activation with additional antioxidant and poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitory actions. Most recently, cilostazol has been shown to prevent vacuolation and rarefaction in the white matter of the rats subjected to chronic cerebral hypoperfusion in association with suppression of astrocyte and microglial activation. Taken together, recent experimental studies with cilostazol showed promising results in cerebral ischemia and chronic cerebral hypoperfusion.

Figure 1

Chemical structure of cilostazol (6‐[4‐(1‐cyclohexyl‐1H‐tetrazol‐5‐yl)butoxy]3,4‐dihydro‐2(1H)‐quinolinone).

Figure 2

Representative immunohistochemical staining of the CD11b (OX‐42), TNF‐α, superoxide, nitrotyrosine, poly(ADP‐ribose) polymer (PAR), and cleaved caspase‐3‐positive cells in the penumbral region of the vehicle‐ and cilostazol‐treated group in comparison with sham group. Compared with the vehicle group, the OX‐42, TNF‐α, superoxide, nitrotyrosine, PAR, and cleaved caspase‐3‐positive cells in the penumbral region of the cilostazol‐treated group are less prominent at 24 h reperfusion after 2 h MCAO. Little immunoreactivity was shown in the sham groups. Each representative Figure is derived from 4∼6 rat brains of each group. Scale bar = 50 μm.

Figure 3

Neuroprotective mechanisms of cilostazol against focal cerebral ischemia. The neuroprotective potentials of cilostazol are ascribed to its anti‐inflammatory and antiapoptotic effects mediated by scavenging hydroxyl radicals and intracellular ROS, maxi‐K channel opening, and inhibition of PARP activity.