The involvement of free radicals in the casual mechanism of Motor Neurone Disease

Fitzmaurice, P.S. (1996) The involvement of free radicals in the casual mechanism of Motor Neurone Disease. Doctoral thesis, University of Central Lancashire.

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The detoxification of free radicals at a cellular level is crucial for maintaining cell viability. The progressive loss of motor neurones associated with motor neurone disease (MND) may be due to acute or chronic free radical damage causing irreversible cell lesions. Perturbation in the mechanisms involved in the cell's protection against the deleterious effects of free radicals could therefore initiate, or indeed propagate, this damage.
Measurement of the free radical detoxif'ing enzymes superoxide dismutases (copper/zinc superoxide dismutase (SOD I), manganese superoxide dismutase (SOD2), glutathione peroxidase (GSHPx) and catalase (CAT) at the site of motor neurone loss (i.e. the anterior horn in the spinal cord) showed a significant increase in the percentage of SOD2, in MND patients than controls, at the thoracic level. GSHPX activity was approximately 10-fold higher in the white matter of the spinal cord compared to that in the gray matter, whilst CAT activity was approximately 100-fold higher than GSHPX and equally distributed between the white and gray matter of the spinal cord.
The activity of CAT within the central nervous system (CNS) is compartmentalised in microperoxisomes, it is therefore likely that removal of peroxides from the cytoplasm and other cellular organelles is reliant on GSHPx activity, which has a significantly lower activity in the anterior horn of the spinal cord than in other cells.
Xanthine oxidase (XO) activity is a potential source of superoxide (07) (metabolism of xanthine to uric acid by XO produces 07) its subcellular location in the perikatyon of the spinal cord was shown to be associated with mitochondria. Thus the normal generation of 07 accompanied by alteration in superoxide dismutation may lead to increased free radical damage of the mitochondria which might initiate the process of cell death.
8-Hydroxylation of guanosine (indicative of oxidative damage) within the spinal cord from MIND patients was 10-fold higher than that in controls, showing that the nerve perikaiyon in MIND are subject to increased oxidative damage. It is clear therefore that free radical mechanisms play an important role in MIND.

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