title: Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS.
abstract: Exposure to environmental lead (Pb) is a mild risk factor for amyotrophic lateral sclerosis (ALS), a paralytic disease characterized by progressive degeneration of motor neurons. However, recent evidence has paradoxically linked higher Pb levels in ALS patients with longer survival. We investigated the effects of low-level Pb exposure on survival of mice expressing the ALS-linked superoxide dismutase-1 G93A mutation (SOD1(G93A)). SOD1(G93A) mice exposed to Pb showed longer survival and increased expression of VEGF in the ventral horn associated with reduced astrocytosis. Pretreatment of cultured SOD1(G93A) astrocytes with low, non toxic Pb concentrations upregulated VEGF expression and significantly abrogated motor neuron loss in coculture, an effect prevented by neutralizing antibodies to VEGF. The actions of Pb on astrocytes might explain its paradoxical slowing of disease progression in SOD1(G93A) mice and the improved survival of ALS patients. Understanding how Pb stimulates astrocytic VEGF production and reduces neuroinflammation may yield a new therapeutic approach for treating ALS.
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, 11800, Montevideo, Uruguay.
authors.forename: Ana G
authors.initials: AG
authors.lastname: Barbeito
authors.forename: Laura
authors.initials: L
authors.lastname: Martinez-Palma
authors.forename: Marcelo R
authors.initials: MR
authors.lastname: Vargas
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.forename: Nelly
authors.initials: N
authors.lastname: Mañay
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
authors.forename: Patricia
authors.initials: P
authors.lastname: Cassina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D007854:Lead / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D042461:Vascular Endothelial Growth Factor A; D007854:Lead; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1