“A 24-hour exposure to 50 µg/L mercury induced significant cell cytotoxicity in neuroblastoma cells. Treatment of cells with melatonin before administration of mercury greatly reduced the mercury-induced cytotoxicity. Mercury treatment of cells produced another as yet undocumented phenomenon, that of inducing oxidative stress, as measured by the loss of reduced glutathione (GSH) from cells. This was a rapid process, requiring only 30 minutes of exposure to mercury. Similarly, pretreating the cells with melatonin...before administration protected cells from the mercury-induced oxidative stress. Melatonin’s mechanism of action is at present unclear; however, melatonin is known to bind heavy metals (Limson et al., 1998REF15) and to increase intracellular GSH levels through an up-regulation of GSH-synthesizing enzymes (Todoroki et al., 1998REF3). It is thus possible to speculate on two mechanisms for melatonin’s antioxidant action, namely, (a) melatonin as a chelating agent binding mercury, thus eliminating its cytotoxic properties, or (b) melatonin causing production of increased levels of intracellular antioxidants such as glutathione (Todoroki et al., 1998REF30). It is not excluded that both these mechanisms could be operating simultaneously.

“The release of both Aß 1-40 and Aß 1-42 into the culture medium was increased by exposure of SHSY5Y cells to mercury. Melatonin preincubation resulted in a significant decrease in Aß release....Mercury has previously been shown to be a potent inhibitor of enzymes, especially those containing sulfhydryl groups (Edstrom and Mattsson, 1976REF9). Protein kinase C activity in vitro and in brain tissue is markedly reduced in a concentration-dependent manner by mercury (Rajanna et al., 1995REF21).....Mercury induces both Aß production and oxidative stress; thus, the chelation of mercury by melatonin could shift the APP metabolism back toward the secretase pathway, reducing Aß production and the concomitant oxidative stress-inducing effects of mercury and Aß. Aß-Fibrillogenesis is also inhibited by melatonin, thereby potentially reducing the toxic buildup of Aß 1-40 and Aß 1-42 fibrils (Pappolla et al., 1998REF20). Furthermore, melatonin has been shown to reduce the release of soluble APP from cells in culture and to reduce the levels of APP mRNA and other housekeeping protein mRNAs (Song and Lahiri, 1997REF24). These data suggest that melatonin may be involved in metabolic mechanisms regulating APP and other essential cellular protein production, over and above its antioxidant capacity.

“In a similar fashion, mercury induced an increase in tau phosphorylation as compared with untreated cells. Melatonin treatment was able to protect cells from the mercury-induced tau hyperphosphorylation. Mercury’s influence on tau phosphorylation remains unclear; however, it may be an indirect effect via oxidative stress and Aß production. Both Aß and oxidative stress have been shown to influence tau phosphorylation (Busciglio et al., 1995REF6; Takashima et al., 1996REF26)”—Journal of Neurochemistry, Vol. 74, No. 1, 2000 231-236 © 2000 International Society for Neurochemistry.”

Melatonin is concentrated in the mitochondria, and protects them from oxidative damage. Dr. Reiter found melatonin to be 5.9 times more effective than glutathione and 11.3 times more effective than mannitol in fighting dangerous, hydroxyl radicals.

[color:"red"] Melatonin’s mechanism of action is at present unclear; however, melatonin is known to bind heavy metals (Limson et al., 1998REF15) and to increase intracellular GSH levels through an up-regulation of GSH-synthesizing enzymes (Todoroki et al., 1998REF3). It is thus possible to speculate on two mechanisms for melatonin’s antioxidant action, namely, (a) melatonin as a chelating agent binding mercury, thus eliminating its cytotoxic properties, or (b) melatonin causing production of increased levels of intracellular antioxidants such as glutathione (Todoroki et al., 1998REF30). It is not excluded that both these mechanisms could be operating simultaneously.[/color]