Nitric Oxide and Superoxide Contribute to Motor Neuron Apoptosis Induced by Trophic Factor Deprivation

Abstract

Primary cultures of rat embryonic motor neurons deprived of brain-derived neurotrophic factor (BDNF) induce neuronal nitric oxide synthase (NOS) within 18 hr. Subsequently, >60% of the neurons undergo apoptosis between 18 and 24 hr after plating. Nitro-L-arginine and nitro-L-arginine methyl ester (L-NAME) prevented motor neuron death induced by trophic factor deprivation. Exogenous generation of nitric oxide at concentrations lower than 100 nM overcame the protection by L-NAME. Manganese tetrakis (4-benzoyl acid) porphyrin, a cell-permeant superoxide scavenger, also prevented nitric oxide-dependent motor neuron death. Motor neurons cultured without trophic support rapidly became immunoreactive for nitrotyrosine when compared with motor neurons incubated with BDNF, L-NAME, or manganese TBAP. Our results suggest that peroxynitrite, a strong oxidant formed by the reaction of NO and superoxide, plays an important role in the induction of apoptosis in motor neurons deprived of trophic factors and that BDNF supports motor neuron survival in part by preventing neuronal NOS expression.

NO: an inhibitor of cell death

“…45 In this case, L-NAME or L-nitro-arginine actually inhibited apoptosis and supported survival of the motor neurons deprived of BDNF. L-NAME protection was abolished by excess L-arginine.…”

Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

“…At low concentrations NO can protect cells against oxidative stress, presumably by induction of adaptive responses in the form of up-regulation of antioxidant proteins (43,44). In contrast, inhibition of nNOS has been shown to protect rat motor neurons from cell death induced by oxidative stress (45). The findings that inhibition of nNOS in a cell culture model of FALS did not confer resistance to mutant SOD1 toxicity (46) and that blockade of NOS either by chemical means (47) or targeted deletion of the nNOS gene (48) had little effect on disease progression in a transgenic mouse model of human ALS have raised uncertainties regarding the importance of NO production in ALS pathogenesis.…”

Oxidative stress and antioxidative parameters in patients with spinal cord injury: implications in the pathogenesis of disease

“…13 An excessive NO production has cytotoxic effects and induces neuronal apoptosis secondary to neural degeneration and neurodysfunction. 14 Several disorders are associated with oxidative stress that are manifested by LP, protein oxidation and other markers. A study by Liu et al 15 reported that oxidative stress levels increase markedly during the first weeks of strict immobilization after the onset of an SCI.…”