MacEvilly, Conor John; (1992) Lipid peroxidation in tissues and neural fractions during experimental vitamin e deficiency and in patients with friedreich's ataxia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A severe deficiency of vitamin E in man results in a characteristic neurological syndrome which is very similar to that seen in patients with Friedreich’s ataxia (FA). The mechanism(s) of action of vitamin E in neurological tissues is unknown although it is generally accepted to act as a lipid soluble antioxidant. The purposes of this study were to examine lipid peroxidation in (a) the vitamin E deficient rat and (b) autopsy material from patients with FA. A fractionation procedure using brainstem was validated to isolate myelin, an axolemma-enriched fraction (AEF) and a fraction containing the axoplasmic membranes and organelles (M/O). Endogenous lipid peroxidation was assessed by measuring thiobarbituric acid reactive substances (TBARS), free, bound and total malondialdehyde (MDA) and aliphatic aldehydes. Susceptibility to in-vitro free radical stress was also investigated using the copper sulphate / hydrogen peroxide generating system and measuring free MDA. Endogenous lipid peroxidation was investigated in vitamin E deficient and control rats after 21 and 56 weeks. After 56 weeks concentrations of TBARS in the deficient animals were increased in all tissues except for peripheral nerve. Increases were less in neural than non-neural tissues (<35% and 2 to 4-fold respectively). Bound MDA was elevated in brain and spinal cord from 56 week deficient animals 2 to 5-fold, but although free MDA was also increased in brain there was no increase in the cord. Aliphatic aldehydes showed the greatest increases ( > 6-fold). Lesser changes in lipid peroxidation were seen after 21 weeks of deficiency. These results, therefore, provide evidence of increased lipid peroxidation during vitamin E deficiency. When tissues and fractions from 20 and 60 week old rats were stressed in-vitro using copper sulphate / hydrogen peroxide the following observations were made (a) the deficient samples in contrast to control material did not exhibit a lag phase and (b) the following order of susceptibility to peroxidation was noted: brain > > spinal cord > nerve; M/O > > AEF > myelin. The latter result is consistent with the neuropathology seen in vitamin E deficiency where a primary axonopathy leads to secondary demyelination. In studies of autopsy material from patients with FA, vitamin E concentrations in neural tissues were not significantly different from control values. Studies of lipid peroxidation failed to show any significant differences between patients and controls. The results would, therefore, seem to rule out an antioxidant defect in the aetiology of this disease.

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