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The Journal of Neuroscience, May 15, 1998, 18(10):3708-3714
Nitric Oxide-Dependent Production of cGMP Supports the Survival
of Rat Embryonic Motor Neurons Cultured with Brain-Derived Neurotrophic
Factor
Alvaro G.
Estévez1, 6, 8,
Nathan
Spear1, 6,
J. Anthony
Thompson2, 4, 6,
Trudy L.
Cornwell5,
Rafael
Radi7,
Luis
Barbeito8, 9, and
Joseph S.
Beckman1, 2, 3, 6
Departments of 1 Anesthesiology,
2 Biochemistry and Molecular Genetics,
3 Neuroscience, 4 Surgery, and
5 Pathology, Division of Molecular and Cellular Pathology,
and 6 The University of Alabama at Birmingham Center for
Free Radical Biology, The University of Alabama at Birmingham,
Birmingham, Alabama 35233, and 7 Departamento de
Bioquímica, Facultad de Medicina, 8 Sección
Neurociencias, Facultad de Ciencias, Universidad de la República
11200 Montevideo, Uruguay, and 9 División
Neurobiología Celular y Molecular, Instituto Clemente Estable,
11600 Montevideo, Uruguay
Trophic factor deprivation induces neuronal nitric oxide synthase
(NOS) and apoptosis of rat embryonic motor neurons in culture. We
report here that motor neurons constitutively express endothelial NOS
that helps support the survival of motor neurons cultured with
brain-derived neurotrophic factor (BDNF) by activating the nitric
oxide-dependent soluble guanylate cyclase. Exposure of BDNF-treated
motor neurons to nitro-L-arginine methyl ester
(L-NAME) decreased cell survival 40-50% 24 hr after
plating. Both low steady-state concentrations of exogenous nitric oxide
(<0.1 µM) and cGMP analogs protected BDNF-treated motor
neurons from death induced by L-NAME. Equivalent
concentrations of cAMP analogs did not affect cell survival. Inhibition
of nitric oxide-sensitive guanylate cyclase with 2 µM
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the
survival of BDNF-treated motor neurons by 35%. cGMP analogs also
protected from ODQ-induced motor neuron death, whereas exogenous nitric
oxide did not. In all cases, cell death was prevented with caspase
inhibitors. Our results suggest that nitric oxide-stimulated cGMP
synthesis helps to prevent apoptosis in BDNF-treated motor neurons.
Key words:
motor neurons; BDNF; endothelial nitric oxide synthase; nitric oxide; apoptosis; guanylate cyclase soluble; cGMP
Copyright © 1998 Society for Neuroscience 0270-6474/98/18103708-07$05.00/0
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