Prolyl hydroxylase domain inhibitors: can multiple mechanisms be an opportunity for ischemic stroke?

Abstract

Stroke and cerebrovascular disease are now the fifth most common cause of death behind other diseases such as heart, cancer and respiratory disease and accounts for approximately 40-50 fatalities per 100,000 people each year in the United States. Currently the only therapy for acute stroke, is intravenous administration of tissue plasminogen activator which was approved in 1996 by the FDA. Surprisingly no new treatments have come on the market since, although endovascular mechanical thrombectomy is showing promising results in trials. Recently focus has shifted towards a preventative therapy rather than trying to reverse or limit the amount of damage occurring following stroke onset. During one of the components of ischemia, hypoxia, a number of physiological changes occur within neurons which include the stabilization of hypoxia-inducible factors. The activity of these proteins is regulated by O₂, Fe²⁺, 2-OG and ascorbate-dependant hydroxylases which contain prolyl-4-hydroxylase domains (PHDs). PHD inhibitors are capable of pharmacologically activating the body's own endogenous adaptive response to low levels of oxygen and have therefore become an attractive therapeutic target for treating ischemia. They have been widely used in the periphery and have been shown to have a preconditioning and protective effect against a later and more severe ischemic insult. Currently there are a number of these agents in phase 1, 2 and 3 clinical trials for the treatment of anemia. In this review we assess the neuroprotective effects of PHD inhibitors, including dimethyloxalylglycine and deferoxamine and suggest that not all of their effects in the CNS are HIF-dependent. Unravelling new roles and a better understanding of the function of PHD inhibitors in the CNS may be of great benefit especially when investigating their use in the treatment of stroke and other ischemic diseases.

Keywords: Hypoxia; Post-conditioning; Preconditioning; Prolyl hydroxylase domain; Stroke; Synaptic transmission.