Depletion of reduced glutathione occurs in the substantia nigra in Parkinson's disease and in incidental Lewy body disease (presymptomatic Parkinson's disease) which may implicate oxidative stress in the neurodegenerative process. In this study mercury orange fluorescent staining and immunostaining with an antibody to reduced glutathione have been used to determine the distribution of reduced glutathione in the substantia nigra in Parkinson's disease compared with normal individuals. Mercury orange staining showed moderate background levels of fluorescence in the neuropil in both control and Parkinson's disease substantia nigra and localised reduced glutathione to the somata of melanized nigral neurons and glial elements of the neuropil. Neuronal nuclei revealed a relative lack of fluorescence after mercury orange staining. There was a significant depletion of reduced glutathione in surviving neurons in Parkinson's disease compared to nerve cell populations in control tissue. Mercury orange fluorescence indicated a high concentration of reduced glutathione in a subpopulation of non-neuronal cells, most likely astrocytes or microglia. Immunohistochemical examination of nigral tissue from the same Parkinson's disease and control patients with an antibody to glutathione showed staining in neuronal perikarya and axonodendritic processes of melanized nigral neurons which was generally most intense in control neurons. Moderately intense staining of the background neuropil, most prominent in control nigras, and staining of capillary walls was also detected. Intense staining was seen in cells with the morphological features of glial cells in both control and PD nigra. These data show a significant presence of reduced glutathione in the cell bodies and axons of nigral neurons. They are in agreement with biochemical studies showing depletion of reduced glutathione in substantia nigra in Parkinson's disease, and indicate a significant loss of neuronal reduced glutathione in surviving nigral neurons in Parkinson's disease.

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The underlying mechanism of cell death in substantia nigra of Parkinson's disease patients remains unknown. Biochemical changes occurring in substantia nigra in Parkinson's disease (increased iron levels, inhibition of complex I activity and decreased reduced glutathione levels; GSH) suggest that oxidative stress and free radical species may be involved. In particular, a decrease in GSH levels may be an early component of the process, since this also occurs in incidental Lewy body disease (presymptomatic Parkinson's disease). GSH is lost only from the substantia nigra in Parkinson's disease and this does not occur in other neurodegenerative disorders of the basal ganglia. GSH loss appears to be global throughout the substantia nigra and not localized to either the glia or neuronal elements. The activity of enzymes involved in the glutathione cycle are normal with the exception of gamma-glutamyltranspeptidase, the activity of which is increased. This could result in increased removal and degradation of glutathione from cells. Depletion of GSH in rat using L-buthionine-[S, R]-sulfoxamine (BSO) potentiates 6-hydroxydopamine (6-OHDA) toxicity but does not in itself produce degeneration of the nigrostriatal pathway. Oxidative stress may be a potentially important factor in the degeneration of the substantia nigra in Parkinson's disease and warrants further investigation into its role in this process.

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OBJECTIVE:To investigate whether the favourable cardiovascular disease (CVD) risk factor profile of habitual exercisers is attributable to exercise or leanness. DESIGN: Cross-sectional study of 113 nonsmoking men aged 30-45 y. CVD risk factors were compared in exercisers (n ¼ 39) and sedentary men (n ¼ 74), and in subgroups of lean exercisers (n ¼ 37), lean sedentary men (n ¼ 46) and obese sedentary men (n ¼ 28). Waist girth was used to identify lean (o100 cm) and abdominally obese (Z100 cm) subgroups. MEASUREMENTS: Blood pressure, physical activity (7-day recall), physical fitness (maximum oxygen consumption) and fasted lipoproteins, apolipoprotein (apo) B, triglycerides, glucose and fibrinogen. RESULTS: Exercisers were fitter and leaner than sedentary men and had a better CVD risk factor profile. Total cholesterol, LDLcholesterol and apo B concentrations were lower in lean exercisers than in lean sedentary men, suggesting that exercise influences these risk factors. Indeed, time spent in vigorous activity was the only significant predictor of total cholesterol and LDL-cholesterol in multiple linear regression models. Exercise status had little influence on triglycerides and HDL-cholesterol (HDL-C), and unfavourable levels were only evident among obese sedentary men. Waist girth was the sole predictor of triglycerides and HDL-C, explaining 44 and 31% of the variance, respectively. CONCLUSIONS: These findings suggest that the CVD risk factor profile of habitual exercisers is attributable to leanness and exercise. Leanness is associated with favourable levels of HDL-C and triglycerides, while exercise is associated with lower levels of total cholesterol, LDL-cholesterol and apo B.

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Habitual exercisers enjoy considerable protection from coronary heart disease (CHD). Often, however, only modest differences in traditional CHD risk factors are apparent between habitual exercisers and their sedentary counterparts. For this reason, there is increasing interest in novel predictors of CHD, such as a preponderance of small, dense low-density lipoprotein (LDL) particles. Polyacrylamide gel electrophoresis was used to separate lipoprotein subfractions in 32 lean exercisers, 36 lean sedentary men and 21 obese sedentary men aged 30 - 45 years. Well-validated equations were used to determine LDL concentration and peak particle diameter. Waist girth was used to identify lean (< 100 cm) and obese (>or= 100 cm) individuals. LDL concentration was lower in lean exercisers than in lean sedentary men (2.64 +/- 0.44 vs. 3.76 +/- 0.79 mmol . l (-1), p < 0.001), suggesting that habitual exercise influences this risk factor. In contrast, there were no significant differences in LDL peak particle diameter between lean exercisers, lean sedentary men and obese sedentary men (27.92 +/- 0.67, 28.09 +/- 0.62 and 27.77 +/- 0.77 nm, respectively). In multiple linear regression analysis, triglyceride concentration was the only significant predictor of LDL PPD. These data suggest that habitual exercise influences LDL concentration but does not influence LDL particle size in men aged 30 - 45 years.