Abstract
It has been proposed that senescence may be associated with changes associated with oxidative damage to macromolecules. Levels of cerebellar nitric oxide synthase (NOS) and rates of generation of cortical reactive oxygen species (ROS), have been determined in mice of various ages. Both of these parameters were significantly reduced in mice aged 9 months relative to 3-month-old mice. In order to determine whether dietary manipulation can modulate these changes, the effect of exposure of mice to differing diets incorporating various antioxidants, was examined. These diets were given to 3-month-old mice for a total period of 6 further months. The presence of melatonin (40 ppm) in the basal diet restored both NOS and ROS levels to the corresponding values found in the younger (3-month-old) group of mice while lipoic acid (1650 ppm) also restored levels of NOS to those found in 3-month-old animals. Addition of coenzyme Q (ubiquinone), 200 ppm or α-tocopherol (1000 ppm) to the basal diet had no effect on either NOS levels or ROS generation. These data suggest that dietary supplementation may aid in delaying onset of metabolic changes characteristic of the older brain. In behavioral testing, older (9-month-old) animals exhibited reduced motor activity and diminished recall ability on the second day of exposure to the test paradigm. While no diet altered motor activity or improved recall of older animals, lipoic acid or tocopherol treatment adversely affected place recall familiarity.
Highlights
Manganese toxicity, or manganism, can trigger severe psychiatric and extrapyramidal motor dysfunction, which have frequently been attributed to oxidative damage
The site-specificity of the pathology and the selective targeting of dopamine have led to the comparison of manganese-induced neurodegeneration to that of other transition metals, iron and copper (Triggs and Willmore, 1984; Rauhala and Chiueh, 2000; Sengstock et al, 1993), i.e. the toxicity of manganese has been associated with the general propensity of transition metals to produce cytotoxic levels of free-radicals during redox cycling
In spite of claims that manganese is a pro-oxidant, experimental efforts to investigate the role of the metal in oxidative stress have largely ignored the relationship between valence and the capacity to promote reactive oxygen species (ROS) formation
Summary
Manganism, can trigger severe psychiatric and extrapyramidal motor dysfunction, which have frequently been attributed to oxidative damage. The reduction of copper-dependent low-density lipoprotein conjugation (Tsujimoto et al, 1988), and iron-induced phospholipid peroxidation, by Mn2+ has been demonstrated in mammalian cultured cells (Tampo and Yonaha, 1992) These protective effects contradict reports of a pro-oxidant role for manganese in the divalent state. In the presence of a trivalent chelator, the apparent ability of divalent manganese to promote the formation of reactive oxygen species (ROS) disappeared These observations were complemented by the finding that trivalent manganese increased the rate of iron oxidation, whereas Mn2+ did not alter the ratio of ferrous to ferric. This suggests a mechanism by which manganese has the capacity to be either a pro-oxidant or an anti-oxidant, and highlights the significance of valence and ion speciation in manganese-related oxidative events
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