Abstract
We studied hypoxic preconditioning (HxP) in the murine developing brain, focusing on the role for vascular endothelial growth factor (VEGF). Newborn mice were used as follows: (1) HxP (or normoxia) then intracerebral (i.c.) NMDA or AMPA-kainate agonist; (2) HxP then intraperitoneal (i.p.) anti-VEGFR2/Flk1 or anti-VEGFR1/Flt1 monoclonal blocking antibody (mAb) then i.c. NMDA/AMPA-kainate agonist; (3) i.p. VEGF then i.c. NMDA/AMPA-kainate agonist; and (4) in mutants lacking the hypoxia-responsive element (HRE) of the VEGF-A gene (VEGF( partial differential/ partial differential)) and their wild-type littermates (VEGF(+/+)), HxP followed by i.c. NMDA agonist. HxP reduced the size of NMDA-related cortical and AMPA-kainate-related cortical and white matter excitotoxic lesions. Anti-VEGFR2/Flk1 mAb prevented HxP-induced neuroprotection. VEGF produced dose-dependent reduction in cortical lesions. HxP did not prevent, but instead exacerbated, brain lesions in VEGF( partial differential/ partial differential) mutants. Thus, exogenous as well as endogenous VEGF reduces excitotoxic brain lesions in the developing mouse. The VEGF/VEGFR2/Flk1 pathway is involved in the neuroprotective response to HxP.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aging / physiology
-
Alanine / analogs & derivatives
-
Alanine / pharmacology
-
Animals
-
Animals, Newborn / physiology*
-
Antibodies, Blocking / pharmacology
-
Brain / growth & development
-
Brain / pathology
-
Excitatory Amino Acid Agonists
-
Hypoxia, Brain / pathology
-
Hypoxia, Brain / physiopathology*
-
Ibotenic Acid
-
Injections, Intraperitoneal
-
Mice
-
Mice, Transgenic
-
Mutation / physiology
-
Promoter Regions, Genetic / genetics
-
Pyrimidinones / pharmacology
-
Recombinant Proteins / administration & dosage
-
Recombinant Proteins / pharmacology
-
Uracil / pharmacology
-
Vascular Endothelial Growth Factor A / genetics
-
Vascular Endothelial Growth Factor A / pharmacology
-
Vascular Endothelial Growth Factor A / physiology*
-
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
-
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
-
Weight Loss / drug effects
Substances
-
Antibodies, Blocking
-
Excitatory Amino Acid Agonists
-
Pyrimidinones
-
Recombinant Proteins
-
Vascular Endothelial Growth Factor A
-
willardiine
-
Ibotenic Acid
-
Uracil
-
Vascular Endothelial Growth Factor Receptor-1
-
Vascular Endothelial Growth Factor Receptor-2
-
Alanine