title: Delayed administration of VEGF rescues spinal motor neurons from death with a short effective time frame in excitotoxic experimental models in vivo.
abstract: VEGF (vascular endothelial growth factor) prevents neuronal death in different models of ALS (amyotrophic lateral sclerosis), but few studies have addressed the efficacy of VEGF to protect motor neurons after the onset of symptoms, a critical point when considering VEGF as a potential therapeutic target for ALS. We studied the capability of VEGF to protect motor neurons after an excitotoxic challenge in two models of spinal neurodegeneration in rats induced by AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) administered either chronically with osmotic minipumps or acutely by microdialysis. VEGF was administered through osmotic minipumps in the chronic model or injected intracerebroventricularly in the acute model, and its effects were assessed by immunohistochemical and histological analyses and motor performance tests. In the chronic model, VEGF stopped the progression of the paralysis and protected motor neurons when administered after AMPA before the onset of the motor symptoms, whereas no protection was observed when administered after the onset. VEGF was also protective in the acute model, but with a short time window, since the protection was effective when administered 1 h but not 2 h after AMPA. Our results indicate that while VEGF has an indubitable neuroprotective effect, its therapeutic potential for halting or delaying the progression of motor neuron loss in ALS would likely have a short effective time frame.
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, DF, Mexico.
authors.forename: Luis B
authors.initials: LB
authors.lastname: Tovar-y-Romo
authors.forename: Ricardo
authors.initials: R
authors.lastname: Tapia
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology; D010243:Paralysis / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D013118:Spinal Cord Diseases / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D042461:Vascular Endothelial Growth Factor A; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002795:Choline O-Acetyltransferase