HIF prolyl hydroxylase inhibitors prevent neuronal death induced by mitochondrial toxins: therapeutic implications for Huntington's disease and Alzheimer's disease.
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-1alpha mRNA is dramatically induced by mutant huntingtin, HIF-1alpha 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 HIF-dependent 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-1alpha 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.
Niatsetskaya
Zoya
Z
Burke-Cornell Medical Research Institute, White Plains, New York 10605, USA.
Basso
Manuela
M
Speer
Rachel E
RE
McConoughey
Stephen J
SJ
Coppola
Giovanni
G
Ma
Thong C
TC
Ratan
Rajiv R
RR
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006816:Huntington Disease / Q000188:drug therapy*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009574:Nitro Compounds / Q000633:toxicity; D018384:Oxidative Stress; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011422:Propionates / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; D011393:Procollagen-Proline Dioxygenase; C015392:3-nitropropionic acid