Increased levels of monoamine-derived potential neurotoxins in fetal rat brain exposed to ethanol.

Pregnant SD rats were exposed to ethanol (25 % (v/v) ethanol at 1.0, 2.0 or 4.0 g/kg body weight from GD8 to GD20) to assess whether ethanol-derived acetaldehyde could interact with endogenous monoamine to generate tetrahydroisoquinoline or tetrahydro-beta-carboline in the fetuses. The fetal brain concentration of acetaldehyde increased remarkably after ethanol administration (2.6 times, 5.3 times and 7.8 times as compared to saline control in 1.0, 2.0 and 4.0 g/kg ethanol-treated groups, respectively) detected by HPLC with 2,4-dinitrophenylhydrazine derivatization. Compared to control, ethanol exposure induced the formation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol, Sal), N-methyl-salsolinol (NMSal) and 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (6-OH-MTHBC) in fetal rat brains. Determined by HPLC with electrochemical detector, the levels of dopamine and 5-hydroxytryptamine in whole fetal brain were not remarkably altered by ethanol treatment, while the levels of homovanillic acid and 5-hydroxyindole acetic acid in high dose (4.0 g/kg) of ethanol-treated rats were significantly decreased compared to that in the control animals. 4.0 g/kg ethanol administration inhibited the activity of mitochondrial monoamine oxidase (51.3 % as compared to control) and reduced the activity of respiratory chain complex I (61.2 % as compared to control). These results suggested that ethanol-induced alteration of monoamine metabolism and the accumulation of dopamine-derived catechol isoquinolines and 5-hydroxytryptamine-derived tetrahydro-beta-carbolines may play roles in the developmental dysfuction of monoaminergic neuronal systems.

Acute and subacute toxicity of tyramine, spermidine, spermine, putrescine and cadaverine in rats.

The acute and subacute toxicity of five biogenic amines-tyramine, spermidine, spermine, putrescine and cadaverine-were examined in Wistar rats. Tyramine and cadaverine had a low acute oral toxicity of more than 2000 mg/kg body weight. Putrescine had an acute oral toxicity of 2000 mg/kg body weight and spermidine and spermine each of 600 mg/kg body weight. All amines investigated caused a dose-related decrease in blood pressure after intravenous administration, except for tyramine, where an increase was found. In 6-wk studies the biogenic amines were administered in the diet to groups of 10 male and 10 female rats. Tyramine and cadaverine were given at levels of 0, 200, 2000 or 10,000 ppm, spermine and putrescine at levels of 0, 200, 2000 or 5000 ppm and spermidine at levels of 0, 20, 200 or 500/1000 ppm in the first study and at levels of 0 or 10,000 ppm in a second study. Spermine was the most toxic. The high dose level showed a great number of changes, such as emaciation, aggressiveness, convulsions and paralysis of the hind legs. Growth, food intake and water intake were considerably decreased. Slight anaemia (males) and changes in plasma clinical chemistry occurred. The relative weights of the thyroid, adrenals, spleen and heart were increased and that of the liver decreased. Impaired kidney function, together with renal histopathological changes and changes in plasma electrolytes and urea, occurred with spermine. Histopathological examinations also revealed decreased glycogen content in the liver, reduction of spermatogenesis, severe depletion of splenic white pulp, acute involution of the thymus and moderate myocardial degeneration in the heart. Myocardial degeneration was also seen in one mid-dose male. Adverse effects were also observed in the top dose groups of all other amines. Decreased body weights associated with diminished food intake were generally seen. Slight increases in packed cell volume, haemoglobin concentration and thrombocytes occurred with cadaverine. With spermidine, decreased plasma creatinine, calcium and inorganic phosphate were observed and decreased potassium levels with cadaverine. The no-observed-adverse-effect level was 2000 ppm (180 mg/kg body weight/day) for tyramine, cadaverine and putrescine, 1000 ppm (83 mg/kg body weight/day) for spermidine and 200 ppm (19 mg/kg body weight/day) for spermine.

Molecular mechanism of monoamine toxicity in Parkinson's disease: hypothetical cell death model.

Although there have been experimental approaches to understanding the etiology of Parkinson's disease, the cause of cell degeneration in this neurological disorder remains a mystery. Herein, a hypothetical model is proposed to explain the mechanism leading neurons to die. The model is based on recent experimental evidence and it attempts to dissect the actions of dopamine and metal ions as potential triggers for the activation of an ordered cascade of events of the cell death machinery.