Prophylactic neuroprotection against stroke: low-dose, prolonged treatment with deferoxamine or deferasirox establishes prolonged neuroprotection independent of HIF-1 function.
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.
Department of Neurology, Center for Neural Development and Disease, The Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Yanxin
Y
Zhao
David A
DA
Rempe
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D000077588:Deferasirox; D003676:Deferoxamine / Q000008:administration & dosage / Q000627:therapeutic use*; D004921:Erythropoietin / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020521:Stroke / Q000378:metabolism / Q000517:prevention & control*; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D001565:Benzoates; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051793:Hypoxia-Inducible Factor 1; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D014230:Triazoles; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003676:Deferoxamine; D000077588:Deferasirox
Genesis. 2001 Oct;31(2):85-94
11668683
Blood Rev. 2008 Dec;22 Suppl 2:S35-41
19059055
Lancet. 2007 Jan 27;369(9558):283-92
17258668
Stroke. 1993 Jan;24(1):117-21
8418534
J Neurosci. 2009 Jul 8;29(27):8828-38
19587290
Neurology. 2000 Aug 22;55(4):490-7
10953179
Cardiovasc Res. 2008 Feb 1;77(3):463-70
18006459
J Cereb Blood Flow Metab. 2011 Jan;31(1):132-43
20407463
NeuroRx. 2004 Jan;1(1):36-45
15717006
J Pathol. 2005 Jul;206(3):291-304
15906272
Curr Drug Targets. 2007 Jul;8(7):846-9
17630938
Gene Expr. 2003;11(3-4):181-97
14686790
Lancet Neurol. 2008 Oct;7(10):875-84
18757238
Stroke. 2002 Sep;33(9):2297-303
12215602
Stroke. 2001 Apr;32(4):980-6
11283400
Stroke. 1994 May;25(5):1075-80
8165683
Stroke. 2004 Nov;35(11 Suppl 1):2687-9
15472113
Cancer Res. 2000 Aug 1;60(15):4010-5
10945599
Genesis. 2006 Jan;44(1):44-9
16419044
J Biol Chem. 2007 Jun 1;282(22):16187-201
17420250
Brain Res. 2007 Oct 24;1176:143-50
17904110
J Neurosci Res. 2006 Jan;83(1):19-27
16307446
J Appl Physiol (1985). 2000 Apr;88(4):1474-80
10749844
Genes Dev. 2001 Apr 1;15(7):859-76
11297510
Neurology. 2004 Jun 8;62(11):2015-20
15184607
J Biol Chem. 2005 Dec 16;280(50):41732-43
16227210
J Ocul Pharmacol Ther. 2008 Dec;24(6):527-35
19046123
Autophagy. 2008 May;4(4):534-6
18376135
Stroke. 2003 Aug;34(8):1981-6
12829864
J Neurosci. 2006 Sep 13;26(37):9471-81
16971531
J Neurosci. 1999 Nov 15;19(22):9821-30
10559391
Stroke. 2005 Apr;36(4):720-3
15731465
Antioxid Redox Signal. 2010 Apr;12(4):435-43
19659431
J Neurosci. 2007 Jun 6;27(23):6320-32
17554006
NeuroRx. 2004 Jan;1(1):46-70
15717007
J Clin Invest. 2009 Nov;119(11):3373-83
19809162
Drug Metab Dispos. 2008 Dec;36(12):2523-38
18775980