Pharmacological Strategies that Affect HIF-1 in the Ischemic Brain: Focus on Hydroxylases Activity and Protein Kinase Pathways

Abstract

Ischemic stroke is a leading cause of morbidity and mortality worldwide which incidence is increasing with society aging. Unfortunately, despite intensive research in treatments to reduce mortality and the severity of the cerebrovascular injury, there are not effective therapies available. Hypoxia-Inducible Factor-1 (HIF-1) triggers the overexpression of genes coding for proteins involved in the adaptative response of the cell to oxygen deprivation. The functional HIF unit is a heterodimeric protein composed of the two subunits, HIF-1alpha and HIF-1beta. HIF-1alpha activity is regulated through different mechanisms involving post-transcriptional and post-translational modifications. During normoxia, prolyl hydroxylases modify HIF-1alpha and marks it for proteasomal degradation. Under hypoxia, reduced activity of prolyl hydroxylases allows stabilization of HIF-1alpha and increases protein levels. Also, several transduction pathways have been proposed to act downstream of putative oxygen sensors and lead to HIF-1alpha phosphorylation by kinases. Collectively, these modifications regulate HIF-1alpha activity inducing gene expression associated with brain protection after ischemia. In this review, we summarize some of the latest compounds that have shown to regulate HIF function and induce protection in brain cells subjected to ischemia. We focus on compounds that target HIF hydroxylases and the PI-3K/Akt and the MAPK/ERK pathways. Increased HIF-1alpha expression holds great promise for the treatment of cerebral ischemia and makes HIF hydroxylases and kinases attractive therapeutic targets. The reduced number of reports associated to the study of kinases and HIF-1alpha in brain, points out the need of further investigation. Keywords: Cerebral ischemia, HIF-1alpha, MAPK/ERK, PI-3K/Akt, prolyl hydroxylases inhibitors, brain ischemia, Hypoxia-Inducible Factor-1 (HIF-1a), prolyl hydroxylases (PH), phosphoinositide 3-kinase (PI-3k), mitogen activated protein kinases (MAPK), Prolil hydroxylation inhibition, Asparaginil hydroxylation inhibition, TM6008, TM6089, Ethyl 3,4-dihydroxybenzoato (EDHB), Deferoxamine (DFO), Metal Ions, Cobalt chloride (CoCl2), Ginkgolides, Baicalein, Clioquinol, Zinc, Erytrhopoietin, hypoxia, HIF-1 phosphorylation, PH inhibitors, Tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), MCAO, chemical hypoxia, ischemic stroke