Depressants, phospholipid metabolism

Some interactions between lithium and other drugs are beneficial. In approximately 60% of depressed patients in whom conventional treatment has failed, the combination of lithium and antidepressant drugs proves successful where neither drug was effective alone (190, 193, 196, 197). Combinations of lithium and carbamazepine are also increasingly used in the successful treatment of refractory affective illness (198). This combination is generally safe, though the possibility of neurotoxicity should be considered. One additional potential benefit of the use of lithium in this way is the prevention of leukopenia induced by carbamazepine (199). Inosotol phospholipid metabolism is not affected by carbamazepine, suggesting an alternative locus of action from that of lithium (200). 

There are clear abnormalities of fatty acid concentrations in depression that are distinct from those in schizophrenia (Adams, Lawson, Sanigorski, Sinclair, 1996 Maes et al., 1996 Maes et al., 1999 Peet, Murphy, Shay, Horrobin, 1998 Edwards, Peet, Shay, Horrobin, 1998). Eirst, the abnormalities are present in both plasma and in red cells, raising the possibility that the problem may be in fatty acid metabolism in general, rather than membrane phospholipid metabolism in particular. Second, the abnormalities are specifically deficits in the omega-3 fatty acids EPA, DHA, and docosapentaenoic acid (DPA), and particularly in EPA. In contrast to the situation in schizophrenia, AA levels are either normal or elevated. 

It is apparent that very considerable attempts have been made to relate the pharmacological action of acetylcholine to an effect on phospholipid metabolism. Watkins (1965) has made further suggestions about the relationship of acetylcholine and other possible neurohumoral agents to phospholipids. Acetylcholine and glutamic acid are essentially excitant in nature and act by depolarizing the synaptic membranes, the consequence of an increased permeability to sodiinn ions. Y-Aminobutyric acid is depressant and probably causes an increase in the permeabflity of the membrane to ions other than sodium (probably mainly chloride). The charge distri-... 

Another important aspect of the inflammatory cascade is arachidonic acid metabolism, leading to the synthesis of the proinflammatory prostaglandins and leukotrienes. Through the formation of Upocortin, an inhibitor of phospholipase A2, glucocorticoids depress the release of arachidonic acid from phospholipids and hence the production of arachidonic acid metabolites. 

Copper and Zinc in Aerobic Metabolism. Cytochrome oxidase, the terminal oxidase in the electron transport chain contains an atom of copper. On this enzyme the protons and electrons generated during oxidative metabolism combine with elemental oxygen to form water. During copper deficiency the tissue concentration of cytochrome oxidase is reduced. While the effects of lower cytochrome oxidase activity on exercise has not been described, it is likely that aerobic energy metabolism will be diminished. This effect of copper deficiency was first described in animals with myelin aplasls — the degeneration myelin (86). The oxidative process of phospholipid synthesis, a primary component of myelin, was depressed. Liver mitochondria had impaired respiratory activity (87). Cytochrome oxidase activity was also depressed in brain, heart and liver. 

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

Metabolic effects include interference with the biosynthesis of cystine and cholesterol, depression and stimulation of phospholipid synthesis and, at higher concentrations, inhibitions of serotonin oxidation. A 1981 study did not reveal any decrease in serum cholesterol or increase in serum triglycerides (Kiviluoto et al., 1981). 

Several investigators (Mills and Williams, 1962 Prohaska and Wells, 1974) have observed a marked decrease in the copper content and cytochrome c oxidase activity of neural tissue from copper-deficient animals. Cytochrome c oxidase is a copper-dependent enzyme and the terminal oxidase in the respiratory chain of mitochondria. These facts have led to speculation that the primary lesion in neonatal ataxia is the depression of cytochrome c oxidase, which leads to a diminution of aerobic metabolism and a subsequent decrease in phospholipid and myeline synthesis. Although this hypothesis seems tenable definitive evidence linking the activity of neural cytochrome c oxidase to the production of myelin is lacking. 

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