Saving the Ischemic Penumbra: Potential Role for Statins and Phosphodiesterase Inhibitors

Abstract

Ischemic stroke is the third cause of death and the most common cause of neurological disability. A main target of treatment is the still salvageable tissue surrounding the core of infarction and called "ischemic penumbra". Up to now the only drug approved for the treatment of acute ischemic stroke is recombinant tissue plasminogen activator to achieve early arterial recanalization and hypoxic tissue reperfusion and improve neural function. However, thrombolytic therapy has to be administered soon after the event since its efficacy is time dependent. This intervention also carries an increased risk of hemorrhagic transformation. In the rescue of poorly perfused cerebral regions an important role is played by collateral blood supply through the circle of Willis and through small pial vessels surrounding the lesion. The extent of collateralization is variable and at least in part regulated by the modulation of arteriolar nitric oxide (NO)-dependent endothelial function. Drugs that can improve endothelial function and cerebrovascular reactivity could have a role in collateral formation and infarct volume limitation. Statins affect endothelial NO production demonstrating their potential to influence endothelial NO synthase (eNOS) and in treating stroke. Phosphodiesterase (PDE) inhibitors improve functional recovery after stroke in rats enhancing neuro and synapto genesis and increasing guanosine 3,5-cyclic monophosphate (cGMP). The aim of this review is to highlight the potential of these two classes of drugs in the treatment of acute ischemic stroke by analysing their pharmacological effects and involvement in the NO and cGMP pathways.

Soluble Guanylate Cyclase α1β1 Limits Stroke Size and Attenuates Neurological Injury

“…Drugs that can improve endothelial function and cerebrovascular reactivity were previously shown to limit the infarct volume in rat models of cerebral ischemia16. Furthermore, impaired vascular relaxation in NOS3-deficient mice was previously suggested to affect CBF during cerebral ischemia and to influence stroke size1.…”

Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains

“…The ischemic penumbra, (i.e, brain tissues surrounding the core in focal ischemic stroke) and the sensitive neurons/networks in global cerebral ischemia are still sustained by the diminished blood supply, however. Further damage in these ischemic brain tissues occurs in a delayed manner after cerebral ischemia/stroke (8)(9)(10), responsible for clinical deterioration. Thus, effective postischemic therapy with an extended time window remains one of the greatest challenges to modern medical practice.…”

Preferential Effect of Premorbid Statins on Atherothrombotic Strokes through Collateral Circulation Enhancement

“…Animal studies have suggested that inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) exerts a pleiotropic effect, extending beyond lipid lowering, with reported influence on cerebral hemodynamics, endothelial function, cell proliferation, inflammatory response, platelet function and lipid oxidation [19,20]. …”