Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS

NEUROBIOLOGY OF DISEASE

卷:37

Article

Barbeito, Ana G.¹  Martinez-Palma, Laura¹  Vargas, Marcelo R.²  Pehar, Mariana²  Manay, Nelly³  Beckman, Joseph S.^4,5  Barbeito, Luis²  Cassina, Patricia¹ 

[1] Univ Republica, Fac Med, Dept Histol & Embriol, Montevideo 11800, Uruguay

[2] Inst Pasteur Montevideo, Montevideo, Uruguay

[3] Fac Quim Montevideo, Dept Toxicol, Montevideo, Uruguay

[4] Oregon State Univ, Environm Hlth Sci Ctr, Dept Biochem & Biophys, Corvallis, OR 97331 USA

[5] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA

关键词: Lead;    Amyotrophic lateral sclerosis;    SOD1(G93A);    VEGF;    Astrocytes;   

DOI  :  10.1016/j.nbd.2009.11.007

来源: Elsevier

【 摘 要 】

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. (C) 2009 Elsevier Inc. All rights reserved.

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