Hypoxia inducible factor and erythropoetin as putative neuroprotectants in cerebral ischemia
Zusammenfassung der Projektergebnisse
The development of neuroprotective strategies for acute stroke has been a source of disappointment for the neuroscientific community over the past 20 years. Although there are surely many reasons for this failure, one possible explanation is that most of the tested agents only affect a small number of downstream targets. Studying the innate neuroprotective strategies of the mammalian biological system, as seen in preconditioning studies or as present in the CA3 hippocampal neurons, might be a step forward. A canonical pathway for adapting to hypoxia and ischemia related stress involves the hypoxia-inducible-factor 1 (HIF-1) transcription factor, which is stabilized after hypoxic/ischemic preconditioning. Inhibiting the HIF-prolyl-hydroxylases (PHDs), that negatively regulate the stability of HIF-1α, has become an attractive pharmacological target for the prevention and treatment of cerebral ischemia. In this project it was shown that Dimethyloxalyglycine (DMOG), a known PHD inhibitor is able to induce an adaptive homeostatic and metabolic cellular response in the rat brain by increasing expression of various HIF-1 downstream targets. Treatment with DMOG also conferred protection to cerebral ischemia in models of permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Moreover, it appeared that this protection was at least partially related to a stabilization of HIF-1α and an induced expression of VEGF and eNOS on both mRNA and protein levels. Regional cerebral blood flow (rCBF) was increased after pMCAO and tMCAO in animals with DMOG treatment, an effect which was likely to be mediated as well by the aforementioned HIF targets. Although DMOG, as an unspecific PHD-inhibitor, which is likely to affect other 2-oxoglutarate dependent enzymes involved in many other biological processes, is not a suitable candidate for clinical translation, these results prove the principle of pharmacologically induced prophylaxis and therapy against cerebral ischemia by stabilization of HIF-1. Further studies with more specific and less toxic PHD-inhibitors are on their way. Moreover, studying the differential response to ischemia of PHD-deficient mice will contribute to our understanding of the involvement of the PHD-HIF axis in the pathophysiology of cerebral ischemia.
Projektbezogene Publikationen (Auswahl)
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Dissecting the molecular pathways responsible for the selective vulnerability of CA1 hipoocampal cells following transient forebrain ischemia by proteomic analysis. 5th International Symposium on Neuroprotection and Neurorepair Cerebral Ischemia and Stroke May 17-20, 2008 in Magdeburg, Germany
Papadakis M et al.
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Is the PHD-inhibitor Dimethyloxalylglycine (DMOG) neuroprotective in permanent focal cerebral ischaemia? 5th International Symposium on Neuroprotection and Neurorepair Cerebral Ischemia and Stroke May 17-20, 2008 in Magdeburg, Germany
Nagel S et al.
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Ischemic preconditioning alters the protein profile of CA1pyramidal neurons to induce tolerance to global cerebral ischemia. 5th International Symposium on Neuroprotection and Neurorepair Cerebral Ischemia and Stroke May 17-20, 2008 in Magdeburg, Germany
Hoyte L et al.
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Magnetic resonance imaging (MRI) of inflammation following middle cerebral artery occlusion (MCAO) in the mouse by microparticles of iron oxide (MPIO) 2008 Oxford Biomedical Imaging Festival, 16th September 2008
Hoyte L et al.
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Magnetic resonance imaging (MRI) of inflammation following middle cerebral artery occlusion (MCAO) in the mouse by microparticles of iron oxide (MPIO). 6th FENS Forum of European Neurosciences, Geneva July 12-16 2008
Hoyte L et al.
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NXY-059 for the treatment of acute ischemic stroke. Future Neurology. May 2008 Vol.3 No.3, 229-240
Papadakis M. et al.
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Pharmacological preconditioning with DMOG, a HIF prolyl 4-hydroxylase inhibitor, for focal cerebral ischaemia in rats. 2008 Oxford Biomedical Imaging Festival, 16th September 2008
Nagel S et al.
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Setting up an acute stroke service. Int J Stroke 2008. Aug;3(3):182-7
Reckless I. et al.
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Therapeutic hypothermia in experimental models of focal and global cerebral ischemia and intracerebral hemorrhage. Expert Rev Neurother. 2008 Aug;8(8):1255-68
Nagel S et al.
