Modulatory and protective effects of prolyl hydroxylase domain inhibitors in the central nervous system.

Abstract

Oxygen is essential for all mammalian species, with complex organs such as the brain requiring a large and steady supply to function. During times of low or inadequate oxygen supply (hypoxia), adaptation is required in order to continue to function. Hypoxia inducible factors (HIF) are transcription factors which are activated during hypoxia and upregulate protective genes. Normally, when oxygen levels are sufficient (normoxia) HIFs are degraded by oxygen sensing prolyl hydroxylase domain proteins (PHD), but during hypoxia PHDs no longer exert influence on HIFs allowing their activation. Given that PHDs regulate the activity of HIFs, their pharmacological inhibition through PHD inhibitors (PHDIs) is believed to be the basis of their neuroprotective benefits. This review discusses some of the potential therapeutic benefits of PHDIs in a number of neurological disorders which see hypoxia as a major pathophysiological mechanism. These include stroke, Parkinson's disease, and amyotrophic lateral sclerosis. We also explore the potential neuroprotective benefits and limitations of PHDIs in a variety of disorders in the central nervous system (CNS). Additionally, the activation of HIFs by PHDIs can have modulatory effects on CNS functions such as neurotransmission and synaptic plasticity, mechanisms critical to cognitive processes such as learning and memory.