allopurinol and Amyotrophic-Lateral-Sclerosis

Topics: Amino Acid Transport System X-AG; Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Astrocytes; Cerebral Cortex; Glutamic Acid; Glycoproteins; Humans; Hydrogen Peroxide; Ischemic Attack, Transient; Oxidation-Reduction; Rats; Reactive Oxygen Species; Xanthine; Xanthine Oxidase; Xanthines

Approximately 20% of cases of familial amyotrophic lateral sclerosis are caused by dominant mutations in the Cu,Zn superoxide dismutase. One such mutant, in which histidine #48 has been replaced by glutamine (H48Q), exhibits a novel activity. It can react sequentially with O2- and H2O2 to generate a potent oxidant at its active site, possibly Cu(II)-OH, which then can oxidize urate to the corresponding radical. This O2- -dependent peroxidase activity exerted on a substrate peculiar to motor neurons may be the toxic gain of function which leads to the deleterious consequences of this mutation. G93A, G93R, and E100G were also examined and found not to exert this O2- -dependent peroxidase activity.

Topics: Amyotrophic Lateral Sclerosis; Binding Sites; Cloning, Molecular; Copper; Cytochrome c Group; Escherichia coli; Hydrogen Peroxide; Mutation; Oxidation-Reduction; Recombinant Proteins; Superoxide Dismutase; Superoxides; Uric Acid; Xanthine; Xanthine Oxidase

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterized by upper and lower motoneurone degeneration. Excitotoxicity and oxidative stress have been proposed as possible aetiological factors. We measured the neuronal death induced in rat cortical cell cultures by CSF taken from seven ALS patient and seven control subjects with lumbar radiculopathies. Cultures were exposed to CSF for 48 h at a dilution of 1:4. Some cultures were also exposed to antioxidant drugs, the free radical scavenger vitamin E (250 microM) and the xanthine oxidase inhibitor allopurinol (50 microM), alone or combined. The mean neuronal death rate was 31.8 +/- 3.4% in cultures exposed to ALS CSF and 10.9 +/- 1.8% in cultures exposed to control CSF. The cytotoxicity of ALS CSF was partially blocked by vitamin E (21.6 +/- 3%) or by allopurinol (18.6 +/- 2.7%). The combination of these two antioxidants reduced the toxicity from 31.8 +/- 3.4% to 10.6 +/- 1.7%. The present work suggests that neurotoxicity induced by CSF from patients with ALS indirectly involves free radicals. A combination of allopurinol and vitamin E may be useful in ALS therapy.

Topics: Adult; Aged; Allopurinol; Amyotrophic Lateral Sclerosis; Antioxidants; Cerebrospinal Fluid; Female; Humans; In Vitro Techniques; Male; Middle Aged; Vitamin E

Recently, point mutations in superoxide dismutase 1 (SOD1) have been shown to lead to a subset of autosomal dominantly inherited familial amyotrophic lateral sclerosis (ALS). These findings have led to the hypothesis that defects in oxygen radical metabolism may be involved in the pathogenesis of ALS. Therefore, we decided to analyze other enzymes involved in oxygen radical metabolism for possible involvement in other forms of ALS. We report here analysis of two genes encoding the molybdenum hydroxylases aldehyde oxidase (AO) and xanthine dehydrogenase/oxidase (XDH) for involvement in ALS. Of particular interest, one gene identified as encoding aldehyde oxidase is shown to map to 2q33, a region recently shown to contain a gene responsible for a familial form of ALS with autosomal recessive inheritance (FALS-AR). The AO gene appears to be located within 280,000 bp of simple sequence repeat marker D2S116, which shows no recombination with the FALS-AR locus. The AO gene is highly expressed in glial cells of human spinal cord. In addition, we mapped a gene for XDH to 2p22, a region previously shown to contain a highly homologous but different form of XDH. Neither of these XDH genes appears to be highly expressed in human spinal cord. This evidence suggests that AO may be a candidate gene for FALS-AR.

Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Amyotrophic Lateral Sclerosis; Base Sequence; Chromosome Mapping; Chromosomes, Human, Pair 2; DNA Primers; Genes, Recessive; Humans; Molecular Sequence Data; Polymerase Chain Reaction; Xanthine Dehydrogenase; Xanthine Oxidase