Victor J. Del Brutto, MD

Bieber M, Schuhmann MK, Volz J, Kumar GJ, Vaidya JR, Nieswandt, et al. Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function. Stroke. 2018;50:478–486.

Inhibition of phosphodiesterase-3 (PDE-3) in platelets increases intracellular cAMP levels resulting in blockage of platelet aggregation induced by collagen, adenosine diphosphate, arachidonic acid, and epinephrine. In addition, PDE-3 inhibitors have a pleiotropic effect over blood vessels, which include arteriolar vasodilation, endothelial repair, smooth muscle anti-proliferative effect, and reduction of endothelial inflammatory response.

Although considered to have a central antiplatelet mechanism of action, PDE-3 inhibitors exert its vascular protective effect through the diverse therapeutic targets listed above. Cilostazol, a PDE-3 inhibitor prototype, is often used chronically in patients with peripheral vascular disease, as well as for coronary artery disease and stroke secondary prevention, particularly in Asian countries. There is growing evidence on the long-term efficacy and safety of cilostazol used among patients with non-cardioembolic stroke, especially when used in combination with aspirin or clopidogrel. However, little is known about its neuroprotective effects during acute ischemic injury.

In the current study, Bieber and colleagues used a mouse model of focal cerebral ischemia to demonstrate the benefits of a novel PDE-3 inhibitor (Substance V) administered immediately after the ischemic insult. Authors found that Substance V administration resulted in reduction of inflammatory markers, less pro-apoptotic activity, and stabilization of the blood brain barrier. These effects resulted in clinically relevant better outcomes including reduced infarct volume and improved functionality, without increasing bleeding complications. Interestingly, platelet function was not altered when compared to controls, thus suggesting that the benefit of PDE-3 inhibition is independent to its antithrombotic effect.

The animal model used in this study involved transient occlusion of the middle cerebral artery followed by reperfusion after 60 minutes. Attenuation of reperfusion injury by stabilization of endothelial tight junctions, as well as the attenuation of the inflammatory response caused by free oxygen radicals, are potentially crucial neuroprotective effects exert by PDE-3 inhibitors.  Thinking ahead, these key therapeutic targets may be of relevant importance when reperfusion injury is expected, such as after administration of IV-tPA or successful endovascular recanalization. These subsets of patients represent an interesting target to study the benefits of this drug class acutely after ischemic stroke in humans.