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

Burke-Cornell Medical Research Institute, White Plains, New York 10605, USA.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 09/2009; 12(4):435-43. DOI: 10.1089/ars.2009.2800
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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.

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Available from: Rachel Speer, Oct 16, 2014
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    • "HIF stabilization by DHB, DMOG and DFO prevents oxidative glutamate toxicity in cortical neurones and is neuroprotective during OGD in organotypic hippocampal cultures (Siddiq et al. 2005, Batti et al. 2010)(see Fig. 4). Whilst PHD inhibition is protective to oxidative stress, it can also improve cell viability in response to mitochondrial dysfunction , glutathione depletion and nerve growth factor withdrawal, which is dependent upon extracellular glucose and HIF-2a activity (Siddiq et al. 2005, Lomb et al. 2007, 2009, Tjong et al. 2008, Lee et al. 2009, Batti et al. 2010, Niatsetskaya et al. 2010, Ma et al. 2013). Also, pre-conditioning neurones to the PHD inhibitor DMOG greatly reduces the excitotoxic affect of glutamate (Batti et al. 2010; Fig. 4). "
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    ABSTRACT: In the CNS neurons are highly sensitive to the availability of oxygen. In conditions where oxygen availability is decreased neuronal function can be altered, leading to injury and cell death. Hypoxia has been implicated in a number of central nervous system pathologies including stroke, head trauma, and neurodegenerative diseases. Cellular responses to oxygen deprivation are complex and result in activation of short- and long-term mechanisms to conserve energy and protect cells. Failure of synaptic transmission can be observed within minutes following this hypoxia. The acute effects of hypoxia on synaptic transmission are primarily mediated by altering ion fluxes across membranes, presynaptic effects of adenosine and other actions at glutamatergic receptors. A more long-term feature of the response of neurons to hypoxia is the activation of transcription factors such as hypoxia inducible factor. The activation of hypoxia inducible factor is governed by a family of dioxygenases called hypoxia inducible factor prolyl 4 hydroxylases (PHDs). Under hypoxic conditions, PHD activity is inhibited, thereby allowing hypoxia inducible factor to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Inhibition of PHD activity stabilizes hypoxia inducible factor and other proteins thus acting as a neuroprotective agent. This review will focus on the response of neuronal cells to hypoxia inducible factor and its targets, including the prolyl hydroxylases. We also present evidence for acute effects of PHD inhibition on synaptic transmission and plasticity in the hippocampus. This article is protected by copyright. All rights reserved.
    Acta Physiologica 05/2013; 208(4). DOI:10.1111/apha.12117 · 4.38 Impact Factor
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    • "At first glance, it may seem that halting or preventing progressive neuron death within these affected areas would provide an adequate therapeutic strategy for HD. While efforts to do this are indeed under way (see Mattson & Furukawa, 1996 or Mattson, 2000 for review; Leyva et al., 2010; Niatsetskaya et al., 2010), this approach has, in and of itself, proven insufficient. At best, efforts to block apoptosis-generating mechanisms in HD patients have delayed symptom onset at early stages, yet have failed to ward off motor symptom onset (Vitamin E-related Antioxidant D-α-tocopherol – Peyser et al., 1995; Creatine – Verbessem et al., 2003; Coenzyme Q 10 – Huntington Study Group, 2001). "
    Huntington's Disease - Core Concepts and Current Advances, 02/2012; , ISBN: 978-953-307-953-0
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    • "As such, there is great interest in utilizing PHIs to induce HIF-1 function for acute stroke treatment. Yet, some in vitro studies suggest that PHIs, including DFO, also provide neuroprotection in the absence of HIF-1 function (Niatsetskaya et al, 2010; Siddiq et al, 2009). It is unknown if DFO and similar compounds are effective for prophylactic neuroprotection against stroke and if HIF-1 mediates these putative neuroprotective properties. "
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    ABSTRACT: Prophylactic neuroprotection against stroke could reduce stroke burden in thousands of patients at high risk of stroke, including those with recent transient ischemic attacks (TIAs). Prolyl hydroxylase inhibitors (PHIs), such as deferoxamine (DFO), reduce stroke volume when administered at high doses in the peristroke period, which is largely mediated by the hypoxia-inducible transcription factor (HIF-1). Yet, in vitro experiments suggest that PHIs may also induce neuroprotection independent of HIF-1. In this study, we examine chronic, prophylactic, low-dose treatment with DFO, or another iron chelator deferasirox (DFR), to determine whether they are neuroprotective with this paradigm and mediate their effects through a HIF-1-dependent mechanism. In fact, prophylactic administration of low-dose DFO or DFR significantly reduces stroke volume. Surprisingly, DFO remained neuroprotective in mice haploinsufficient for HIF-1 (HIF-1+/-) and transgenic mice with conditional loss of HIF-1 function in neurons and astrocytes. Similarly, DFR was neuroprotective in HIF-1+/- mice. Neither DFO nor DFR induced expression of HIF-1 targets. Thus, low-dose chronic administration of DFO or DFR induced a prolonged neuroprotective state independent of HIF-1 function. As DFR is an orally administered and well-tolerated medication in clinical use, it has promise for prophylaxis against stroke in patients at high risk of stroke.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2011; 31(6):1412-23. DOI:10.1038/jcbfm.2010.230 · 5.41 Impact Factor
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