VEGF protects spinal motor neurons against chronic excitotoxic degeneration in vivo by activation of PI3-K pathway and inhibition of p38MAPK.

Vascular endothelial growth factor (VEGF) protects spinal motor neurons in models of familial amyotrophic lateral sclerosis. We previously demonstrated that VEGF also prevents motor neuron death and hindlimb paralysis in rats subjected to α-amino-3-hydroxy-5-isoxazolepropionate (AMPA)-induced chronic excitotoxic motor neuron degeneration. Here, we show that tyrosine kinase receptor-2 for VEGF (VEGFR2) is expressed in spinal motor neurons of the adult rat, and that its blockade impedes the VEGF-mediated protection against motor neuron death and paralysis. In addition, inhibition of phosphatidyl-inositol-3-kinase, which is activated by VEGFR2, completely prevented this protection, whereas blockade of mitogen-activated protein kinase kinases resulted only in a partial prevention. We show as well that AMPA induces an increased p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and that VEGF blocks this effect. Furthermore, inhibition of p38MAPK prevents the paralysis induced by AMPA. These results shed light into the mechanisms of the protective effect of VEGF against excitotoxic motor neuron death in vivo and suggest that VEGFR2 and activation of phosphatidyl-inositol-3-kinase or inhibition of p38MAPK might be important therapeutic targets for amyotrophic lateral sclerosis.