There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Friedreich’s ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson’s disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood‐brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.

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Glutathione, oxidative stress and neurodegeneration.

Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death.

Nitric oxide, mitochondria and neurological disease.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. In order to address the question of a putative role of mitochondrial dysfunction in the pathogenesis of ALS, we studied the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain enzyme activities in spinal cords of ALS patients and in control subjects without neuropathologic abnormalities. Using a "double PCR and digestion" technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, we found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls. No large-scale rearrangements were found, but the amount of mtDNA, measured by Southern blot, was significantly lower in the ALS samples. This reduction correlated well with a decrease of citrate synthase (CS) activity, a mitochondrial marker, as were the activities of respiratory chain complexes I + III, II + III, and IV, suggesting a loss of mitochondria in ALS spinal cords.

Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients

Excitotoxicity may play a role in certain disorders of the motor system thought to be caused by environmentally acquired toxins, including lathyrism and domoic acid poisoning. Motor neurons appear to be particularly susceptible to toxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-kainate receptors. There is a body of evidence implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). Interference with glutamate-mediated toxicity is so far the only neuroprotective therapeutic strategy that has shown benefit in terms of slowing disease progression in ALS patients. Biochemical studies have shown decreased glutamate levels in central nervous system (CNS) tissue and increased levels in the cerebrospinal fluid (CSF) of ALS patients. CSF from ALS patients is toxic to neurons in culture, apparently via a mechanism involving AMPA receptor activation. There is evidence for altered expression and function of glial glutamate transporters in ALS, particularly excitatory amino acid transporter 2 (EAAT2). Abnormal splice variants of EAAT2 have been detected in human CNS. Mitochondrial dysfunction may contribute to excitotoxicity in ALS. Induction of neuronal nitric oxide synthase and cyclooxygenase 2 in ALS may also lead to significant interactions with regulation of the glutamate transmitter system. Certain features of motor neurons may predispose them to the neurodegenerative process in ALS, such as the cell size, mitochondrial activity, neurofilament content, and relative lack of certain calcium-binding proteins and molecular chaperones. Motor neurons appear vulnerable to toxicity mediated by calcium-permeable AMPA receptors. The relatively low expression of the glutamate receptor 2 (GluR2) AMPA receptor subunit and the high current density caused by the large number and density of cell surface AMPA receptors are potentially important factors that may predispose to such toxicity.

Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis

The cause of selective degeneration of motor neurons in the ventral horn of the spinal cord associated with amyotrophic lateral sclerosis (ALS) has still not been elucidated. Recently, so-called oxidative stress has been suggested to be a significant factor in the pathogenesis of this disease. We measured the antioxidant actions of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and cytochrome c oxidase (CO) of the human spinal cord in patients with ALS in comparison with those in control patients. Total SOD activity in spinal cord transections from patients with sporadic ALS was not significantly different from the controls in ventral, lateral, or dorsal regions, although enzymic activity was relatively higher in the ventral compared with the dorsal region. GSH-Px activity in the spinal cord of ALS patients was not very different from that in the control tissue. In contrast, CO activity was significantly reduced in all three regions of the spinal cord in patients with ALS, although the reduction was more marked in the ventral region. These results suggest that reactive oxygen species may attack the mitochondrial respiratory chain, leading eventually to the degeneration of vulnerable motor neurons in the spinal cord, even though no obvious changes in the activity of antioxidant enzymes are detectable. © 1996 Wiley-Liss, Inc.

Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis.

M. Honda

Papers

Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis.