methylnitronitrosoguanidine and Nerve-Degeneration

Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells. This protective effect was still observed 8h after glutamate exposure followed by PJ34 treatment. These results suggest that PARP activation plays a critical role in glutamate-induced necroptosis. We also examined the interaction between PARP and a necroptosis inhibitor called necrostatin-1 (Nec-1). Previously, we showed that Nec-1 protects against glutamate-induced oxytosis by inhibiting the translocation of cellular apoptosis-inducing factor (AIF), a downstream target of PARP-1 activation. In this study, Nec-1 reduced PARP activity but had no effect on the expression of PARP-1 in cells treated with glutamate. Nec-1 also did not protect against cell death mediated by the PARP activator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), although PJ34 did protect against MNNG-mediated cell death. These findings suggest that Nec-1 is not a direct PARP inhibitor and that its signaling target is located upstream of PARP.

Topics: Animals; Apoptosis; Apoptosis Inducing Factor; Cell Line, Transformed; Enzyme Inhibitors; Glutamic Acid; Imidazoles; Indoles; Methylnitronitrosoguanidine; Mice; Necrosis; Nerve Degeneration; Neurotoxins; Oxidative Stress; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Lymphoblastoid lines from nine Usher's syndrome (recessively inherited retinitis pigmentosa and congenital sensorineural deafness) patients (representing eight kindreds) and from ten Duchenne muscular dystrophy patients (representing seven kindreds) showed a small but statistically significant hypersensitivity to the lethal effects of X-rays, as measured by the cellular ability to exclude the vital dye trypan blue, when compared with lines from 26 normal control subjects. Fibroblast lines from the Usher's syndrome patients, treated with X-rays or the radiomimetic, DNA-damaging chemical N-methyl-N'-nitro-N-nitrosoguanidine, also showed a statistically significant hypersensitivity when compared to normal fibroblast lines. These findings are consistent with the possibility that defective DNA repair mechanisms may be involved in the pathogenesis of these degenerative diseases.

Topics: Adolescent; Adult; Aged; Ataxia Telangiectasia; Cell Line; Cell Survival; Child; Child, Preschool; Deafness; DNA Repair; Female; Fibroblasts; Humans; Infant, Newborn; Lymphocytes; Male; Methylnitronitrosoguanidine; Middle Aged; Muscular Dystrophies; Nerve Degeneration; Retinitis Pigmentosa

Cells from patients with ataxia telangiectasia, a rare autosomal recessive disease characterized by primary neuronal degeneration, are abnormally sensitive to the DNA-damaging chemical N-methyl-N'-nitro-N-nitrosoguanidine. We have conducted experiments to determine whether more common primary neuronal degenerations also have a hypersensitivity to this radiomimetic chemical. Fibroblast strains from 13 control donors and from 13 patients with inherited primary neuronal degenerations were treated in vitro with the chemical, and the strains' sensitivity to the chemical was then determined by measuring their ability to divide and form colonies. Twelve of the 13 patient strains, including the 6 Huntington disease and the 4 familial dysautonomia strains, were abnormally sensitive. This hypersensitivity, which is believed to reflect defective repair of the chemically-induced DNA damage, might provide the basis for presymptomatic and prenatal diagnostic tests for these disorders and for elucidating their pathogenesis.

Topics: Adolescent; Adult; Cell Division; Cells, Cultured; Child; Child, Preschool; Dysautonomia, Familial; Female; Fetus; Fibroblasts; Humans; Huntington Disease; Infant; Male; Methylnitronitrosoguanidine; Middle Aged; Nerve Degeneration; Nervous System Diseases; Neurons; Pregnancy