Bioenergetics in Oxidative Damage in Neurodegenerative Diseases

  • M. Flint Beal
Part of the GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia book series (GWUN)


A major theory of neuronal damage in neurodegenerative diseases is that activation of excitatory amino acid receptors may play a role. In the case of neurodegenerative diseases activation of excitatory amino acid receptors may occur as a consequence of a defect in energy metabolism, which then leads to partial neuronal depolarization and activation of voltage-dependent NMDA receptors. This leads to calcium influx into the cell which is followed by activation of several deleterious processes. Amongst these are the generation of free radicals by mitochondria and the activation of nitric oxide synthase (NOS), leading to production of nitric oxide. Nitric oxide can react with Superoxide to produce peroxynitrite, which can then damage lipids, proteins and DNA. Consistent with these proposed mechanisms we found that 3-nitropropionic acid, an irreversible succinate dehydrogenase inhibitor, produces selective striatal lesions in both rats and primates by a secondary excitotoxic mechanism. This compound produces striatal lesions and delayed chorea and dystonia following accidental ingestion in mam. We found that it produces energy depletion in the striatum in vivo, and secondary excitotoxic lesions. Chronic low grade systemic administration of 3-nitropropionic acid produces striatal lesions which show age-dependence, spiny neuron dendritic changes, and selective neuronal vulnerability similar to that seen in Huntington’s disease. Administration of 3-nitropropionic acid to primates resulted in apomorphine inducible chorea. Histologic examination with GFAP and calbindin staining showed a dorsal-vental gradient of cell loss, and sparing of NADPH-diaphorase neuron. These lesions therefore closely resemble Huntington’s disease, and in primates there is an apomorphine inducible chorea. The lesions are accompanied by increased hydroxyl radical generation and they are attenu ated by both free radical spin traps and a selective inhibitor of neuronal NOS. The free radical spin traps attenuate hydroxyl radical production, yet they have no effects on striatal energy metabolism or striatal electrophysiologic activity in vivo, arguing against a direct effect on excitatory amino acid receptors. The NOS inhibitor also attenuates MPTP neurotoxicity. Free radical and NOS inhibitors may therefore be useful in the treatment of Huntington’s disease and Parkinson’s disease.


Amyotrophic Lateral Sclerosis Excitatory Amino Acid Receptor Striatal Lesion Mitochondrial Toxin Choreiform Movement 
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Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • M. Flint Beal
    • 1
  1. 1.Neurology ServiceMassachusetts General HospitalBostonUSA

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