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The Journal of Neuroscience, August 1, 2002, 22(15):6401-6407
Neuroprotection by Hypoxic Preconditioning Requires Sequential Activation of Vascular Endothelial Growth Factor Receptor and Akt
Antje Wick1, Wolfgang Wick2, Johannes Waltenberger3, Michael Weller2, Johannes Dichgans1, and Jörg B. Schulz1 Laboratories of 1 Neurodegeneration and 2 Neuro-Oncology, Department of Neurology, University of Tübingen, 72076 Tübingen, Germany, and 3 Department of Internal Medicine II (Cardiology), Ulm University Medical Center, 89081 Ulm, Germany
Hypoxic preconditioning provides protection against ischemic brain lesions in animal models of cerebral ischemia-hypoxia. To analyze the underlying molecular mechanisms, we developed an in vitro model of hypoxic neuroprotection in cerebellar granule neurons (CGN) by reducing the oxygen tension to 1-5% for 1-24 hr. Exposure to 5% O2 for 9 hr resulted in reduction of cell death after potassium deprivation, treatment with 100 µM glutamate, or 500 µM 3-nitroproprioninc acid (3-NP) by 46, 22, and 55%, respectively. Shorter (1 or 3 hr) or longer (>12 hr) intervals or pretreatment with lower oxygen tension failed to rescue CGN from death. In contrast, toxicity of four different chemotherapeutic drugs [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, cisplatine, topotecane, and vincristine] was unaffected by hypoxic preconditioning. The induction of protective effects was dependent on new protein synthesis. Protein levels of B-cell lymphoma protein-2 (BCL-2), BCL-xL/S, heat shock protein 70/90, and BCL-2-associated death protein remained unaltered. CGN incubated at 5% O2 for 9 hr showed increased levels of the vascular endothelial growth factor (VEGF), the VEGF receptor-2 (VEGFR-2), phosphorylated Akt/protein kinase B (PKB), and extracellular signal-regulated kinase 1 (ERK1). Incubation with a neutralizing anti-VEGF antibody, a monoclonal antibody to VEGFR-2, wortmannin, or antisense-Akt/PKB, but not treatment with U0126, an ERK-inhibitor, reverted the resistance acquired by hypoxic preconditioning. Inhibition of VEGFR-2 blocked the activation of Akt/PKB. Finally, pretreatment with recombinant VEGF resulted in a hypoxia-resistant phenotype in the absence of hypoxic preconditioning. Our data are indicating a sequential requirement for VEGF/VEGFR-2 activation and Akt/PKB phosphorylation for neuronal survival mediated by hypoxic preconditioning and propose VEGF as a hypoxia-induced neurotrophic factor.
Key words: neuron; vascular endothelial growth factor; DC101; Akt; antisense oligonucleotide; glutamate; potassium; 3-nitropropionic acid
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156401-07$05.00/0
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