Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory.
A number of studies have established a role for vascular endothelial growth factor (VEGF) in angiogenesis. Recent reports have shown that VEGF overexpression in the hippocampus improves learning and memory and is associated with enhanced neurogenesis. PTK787/ZK222584 (PTK/ZK) is a reported inhibitor of VEGFR signaling that is currently being tested for its effects on lung and colon cancer. However, the influence of this drug on cognition has not been examined. In the present study, we questioned if post-training administration of PTK/ZK influences hippocampus-dependent memory. When administered to rats immediately following massed training in the Morris water maze, PTK/ZK impaired spatial memory retention tested 48 h later. This impairment was evidenced by increased latency to the hidden platform and fewer platform crossings. However, this impairment was not associated with a change in neurogenesis during this time frame. PTK/ZK infusion did not reduce VEGFR or AKT phosphorylation, but increased the phosphorylation of ERK. These studies suggest that VEGFR inhibitors such as PTK/ZK may negatively influence cognition.
Pati
Shibani
S
Department of Neurobiology and Anatomy, The University of Texas Medical School, P.O. Box 20708, Houston, TX 77225, USA.
Orsi
Sara A
SA
Moore
Anthony N
AN
Dash
Pramod K
PK
D000818:Animals; D002404:Catheterization; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D008845:Microinjections; D055495:Neurogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000008:administration & dosage* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases