Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.
Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss of motor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SOD1 activity, possibly potentiated by inefficient glutamate transport.
Rothstein
J D
JD
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Bristol
L A
LA
Hosler
B
B
Brown
R H
RH
Kuncl
R W
RW
D000111:Acetylcysteine / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006801:Humans; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D013116:Spinal Cord / Q000166:cytology* / Q000502:physiology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics
D014151:Anti-Anxiety Agents; D000975:Antioxidants; D002839:Chromans; D005971:Glutamates; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D010879:Piperazines; C061950:GYKI 52466; D001569:Benzodiazepines; C066382:U 78517F; D018698:Glutamic Acid; D004050:Ditiocarb; D013482:Superoxide Dismutase; D002795:Choline O-Acetyltransferase; D000111:Acetylcysteine