Receptor Mechanisms of VEGF-mediated Neuroprotection Following Status Epilepticus
Item
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Title
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Receptor Mechanisms of VEGF-mediated Neuroprotection Following Status Epilepticus
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Identifier
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d_2009_2013:35d12327b37f:12055
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identifier
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12569
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Creator
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Salerni, Elisa A.,
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Contributor
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Susan D. Croll
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Date
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2013
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | Psychology | Psychobiology | hippocampus | neuroprotection | pilocaprine | VEGF | VEGFR1 | VEGFR2
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Abstract
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Vascular endothelial growth factor (VEGF) is an angiogenic factor with known neuroprotective effects. Previous research in our laboratory has shown that intrahippocampal VEGF infusions protect neurons from death 24 hours after status epilepticus (Nicoletti et al., 2008). VEGF is unable to cross the blood brain barrier given its large molecular size, which limits its therapeutic utility in human epilepsy. If the VEGF receptor mediating VEGF's neuroprotective effects could be identified, small molecule reagents targeted to specific receptors may be developed for clinical use. In vitro studies suggest VEGF's neuroprotective effects are mediated by VEGFR2 (Jin et al., 2000; Matsuzaki et al., 2001). To determine which receptor(s) mediate VEGF's neuroprotective effects, we infused VEGF into the hippocampus simultaneously with 1 of 3 different VEGF receptor inhibitors continuously for 5 days prior to pilocarpine-induced status epilepticus. Tissue was taken 24 hours following status epilepticus and CA1 neuronal damage was evaluated using stereological techniques. VEGFR2 receptor inhibition with the tyrosine kinase inhibitor SU1498/SU5416, which blocks VEGF signaling on intracellular and cell surface VEGFR2, did not alter neuroprotection, while blockade of the VEGFR2 binding site with an anti-VEGFR2 antibody significantly worsened neuronal damage. This may suggest a neuroprotective mechanism of VEGF binding to cell surface VEGFR2. While blockade of the VEGF binding site on cell surface VEGFR1 with an anti-VEGFR1 antibody did not influence neuroprotection, we propose that VEGFR1 activation may exacerbate neuronal death via increased permeability and inflammation secondary to seizures. These findings suggest a balance between activation of different VEGF receptors may determine optimal therapeutic utility of VEGF in epilepsy.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Psychology
