HIF Prolyl Hydroxylase Inhibitors Prevent Neuronal Death Induced by Mitochondrial Toxins: Therapeutic Implications for Huntington's Disease and Alzheimer's Disease

Abstract

Mitochondrial dysfunction is a central feature of a number of acute and chronic neurodegenerative conditions, but clinically approved therapeutic interventions are only just emerging. Here we demonstrate the potential clinical utility of low molecular weight inhibitors of the hypoxia inducible factor prolyl-4-hydroxylases (HIF PHDs) in preventing mitochondrial toxin-induced cell death in mouse striatal neurons that express a ''knock-in'' mutant Huntingtin allele. Protection from 3-nitropropionic acid (3-NP, a complex II inhibitor)-induced toxicity by HIF PHD inhibition occurs without rescue of succinate dehydrogenase activity. Although HIF-1a mRNA is dramatically induced by mutant huntingtin, HIF-1a depletion by short interfering RNAs (siRNA) does not affect steady-state viability or protection from 3-NP-induced death by HIF PHD inhibitors in these cells. Moreover, 3-NP-induced complex II inhibition in control or mutant striatal neurons does not lead to activation of HIFdependent transcription. HIF PHD inhibition also protects cortical neurons from 3-NP-induced cytotoxicity. Protection of cortical neurons by HIF PHD inhibition correlates with enhanced VEGF but not PGC-1a gene expression. Together, these findings suggest that HIF PHD inhibitors are promising candidates for preventing cell death in conditions such as Huntington's disease and Alzheimer's disease that are associated with metabolic stress in the central nervous system. Antioxid. Redox Signal. 12, 435-443.

Prophylactic neuroprotection against stroke: Low-dose, prolonged treatment with deferoxamine or deferasirox establishes prolonged neuroprotection independent of HIF-1 function

“…Instead, siRNA directed against prolyl 4-hydroxylase isoform 1 diminished neuronal death induced by oxidative stress through HIF-independent mechanisms (Siddiq et al, 2009). In addition, structurally diverse PHIs (including DFO) protect neurons in an in vitro model of Huntington's disease through a mechanism independent of HIF-1 function (Niatsetskaya et al, 2010). Yet, the molecular processes mediating this protective phenotype are unknown.…”

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

“…In vitro, rotenoneinduced neuronal apoptosis was attenuated and autophagy increased, as the result of enhanced HIF following deferoxamine administration [48]. In vivo, PHD inhibitors have shown promising results in the attenuation of ischemic stroke [49], and might be neuroprotective in metabolic chronic neurodegenerative conditions [50]. However, studies showing inhibition of PHD-1 by ROS suggest non-HIF-mediated neuronal protection under normoxic conditions [51].…”

Oxidative Stress and Altered Mitochondrial Function in Neurodegenerative Diseases: Lessons From Mouse Models

“…PGC-1α is directly deacetylated and activated by sirtuin type1 (SIRT1), a member of the sirtuin family of protein deacetylases [168]. dysfunction and HIF-1α signaling pathway in neurodegeneration [170,171]. Parallel to the caveat outlined above for PD disease, the relevance of these studies using neurotoxic agents as an experimental approach for HD has to be taken cautiously.…”