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The effect of 10-week administration of sabeluzole on the brain function in old rats
405 gluconate was added to drinking water (1 mg/ml) and injected i.p. alone or with tricyelics each day, i.e., 6 h after inescapable shocks on day 1 and then twice a day in the morning and the evening between 18-19h (Martin et al, 1986). Plasma lithium and triiodothyronine ('1"3) levels were determined in each group of rats. Our results were the following: Lithium gluconate (50, 100 mg/kg/day) administered for a short period exhibited antidepressant like effects, Lithium gluconate exhibited an antidepressant-like effect without altering plasma T3 levels The effect of lithium is seen at plasma levels over 0.75 mEg/1 In the co-administration study, a lower dailydose of lithium (25 mg/kg) potentiates the antidepressant effects of imipramine (2 to 8 mg/kg/day); plasma lithium levels, in this study, do not significantly differ from those measured in the group treated with lithium alone. In conclusion, a short-term lithium treatment alone may exhibit antidepressant-like effects. Side effects associated with lithium treatment such as hypothyroidism were not observed. Lithium given in addition to antidepressant drugs may be of use in patients who are refractory to antidepressant therapy alone. This may be a promising strategy encouraging controlled clinical trials. References
Martin, P., Soubde, P. and Simon, P., 1986, Shuttle-box deficits induced by inescapable shocks in rats: reversal by the betaadrenoreceptor stimulants clenbuterol and salbutamol. Pharmacol. Biochem. Behav. 24, 177-181.
The effect of lO-week administration of sabeluzole on the brain function in old rats
Benesova, O., Tejkalova, H., Kristofikova, Z. and Ripova, D. Psychiatric Center Prague, 181 03 Prague 8, Czechoslovakia We have investigated the cognitive efects of sabeluzole in an animal model experiment, using long-term peroral drug administration in old rats and testing behavioural as well as neurobiochemical outcome, according to the previously described experimental protocol (Benesova et al, 1990). Sabeluzole (R 58735), a benzthiazole derivative, has been shown to have effects on cognitive function in animals, elderly volunteers and elderly patients with real memory problems of unknown origin (Tritsmans et al, 1990). The study was carried out in senescent rats, male Wistar, breed Velaz, age 20 months (N~24). Sabeluzole was administered as a mixture to standard diet in the daily dose 10 mg/kg for 10 weeks in 12 animals, the other 12 animals were fed normal diet. In the tenth week of experiment, behavioural tests were performed (open field behaviour, motor performance on rotating cilinder). All rats were then decapitated, the brains quickly removed and dissected in 4 parts (cortex, hippoeampus, hypothalamus, striatum) for biochemical analysis, using previously established biochemical markers of brain aging (Benesova et al, 1989): high-affinity choline uptake (I-IACU), concentrations of noradrenaline, dopamine, serotonin and their metabolites, lipid peroxidation, protein insolubilization. Behavioural tests indicated no difference between experimental and control group in motor performance on the rotating eilinder, but there was a higher rate of open field exploratory activity in sabeluzole treated animals. The brains of these rats exhibited significant differences in monoamine metabolism ( increased noradrenaline concentration in the hypothalamus, activation of dopamine turnover in the striatum and hypothalamus). Cholinergic neuronal activity in the hippocampus (HACU) was not changed. Lipid peroxidation - as the marker of free radical membrane damage - was markedly decreased in the cortex of sabeluzole treated rats, whereas the solubility of cortical membrane proteins did not differ between the two groups. These results suggest that 10-week sabeluzole treatment in old rats might decelerate the progress of behavioural decline and neurobiochemical deterioration in aging brain.
406 References Benesova, O., et al, 1989, Activ. Nerv. Sup. 31,231. Benesova, O., et al, 1990, Aetiv. Nerv. Sup. 32, 53. Tritsmans, L., et al, 1990, Drug Dev. Res. 20, 473.
Caroxazone: a short-acting and reversible monoamine oxidase inhibitor with therapeutic potential for Parkinson's disease
Caccia, C., Carfagna, N., Fornaretto, M.G., Cavanus, S., Mantegani, S., Roncucci R. and Fariello, R.G. CNS Department, Farmitalia Carlo Erba-Erbamont Group, Nerviano, Italy Experimental and clinical studies (Moretti et al, 1981a,b) showed that caroxazone [2-oxo-2H-1,3-benzoxazine-3(4H)acetamide] is a short-acting, reversible monoamine oxidase (MAO) inhibitor. In vitro, in rat brain mitochondria it exhibited a greater specificity towards the form B flCs0=32 and 4 /aM for MAO-A and MAO-B, respectively). Full reversibility of caroxazone MAO-inhibitory activity was confirmed directly by washings and dialysis experiments. In vivo, the decrease in dopamine (DA) and serotonin metabolite levels displayed also some inhibition of MAO-A. This effect was very short-lasting, since enzyme activity and metabolite levels returned to control values 6-9 hrs after oral high doses (50-100 mg/kg). Caroxazone did not affect blood pressure and did not potentiate the tyramine-induced increase in blood pressure even at high doses. In C57B1 mice, caroxazone prevented brain DA depletion induced by lmethyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP). The 70% reduction in striatal DA levels after MPTP was completely prevented by prior administration of caroxazone at 1 and 6 hr, at 9 hr before MPTP no protective effect was displayed due to its reversibility (ED50=5.5 mg/kg orally). In man, caroxazone was well tolerated even at high doses og 600-800 mg and its administration resulted in a dose dependent increase of urinary tryptamine excretion which quickly returned to basal value (tth=3 days) and in a MAO activity inhibition of platelet-rich plasma (t~h=l.5 days). It has been suggested (Cohen and Mytilineou, 1985) that MAO inhibitors prevent MPTP neurotoxieRy either by inhibiting the increased production of hydrogen peroxide associated with MAO-A action on dopamine and/or by preventing the oxidation of MPTP to active metabolites involved in the neurotoxicity (MAO-B). A reversible, mixed MAO inhibition could be beneficial in slowing down neurodegenerative process in Parkinson's Disease and possibly Alzheimer's Disease. Caroxazone would seem to be a suitable therapeutic candidate with interesting potential for these syndromes. References Moretli, A., Caccia, C., Calderini, G., Menozzi, M. and Amico, A., 1981a, Studies on the mechanism of Action of caroxazone, a new antidepressantdrug. Biochem. Pharmacol. 30, 2728. Moretti, A., Caecia, C., Martini, A., Bonollo, L., Amico, A., Sega, R., Nicolella, V. and Nicolis, F.B., 1981b, Effect of caroxazone, a new antidepressantdrug, on monoamineoxidases in healthy volunteers.Br. J. Clin. Pharmac. 11, 511. Cohen, G. and Mytilineou,C., 1985, Studies on the mechanismof Actionof l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). Life Sei. 35, 237.
Martin, P., Soubde, P. and Simon, P., 1986, Shuttle-box deficits induced by inescapable shocks in rats: reversal by the betaadrenoreceptor stimulants clenbuterol and salbutamol. Pharmacol. Biochem. Behav. 24, 177-181.
The effect of lO-week administration of sabeluzole on the brain function in old rats
Benesova, O., Tejkalova, H., Kristofikova, Z. and Ripova, D. Psychiatric Center Prague, 181 03 Prague 8, Czechoslovakia We have investigated the cognitive efects of sabeluzole in an animal model experiment, using long-term peroral drug administration in old rats and testing behavioural as well as neurobiochemical outcome, according to the previously described experimental protocol (Benesova et al, 1990). Sabeluzole (R 58735), a benzthiazole derivative, has been shown to have effects on cognitive function in animals, elderly volunteers and elderly patients with real memory problems of unknown origin (Tritsmans et al, 1990). The study was carried out in senescent rats, male Wistar, breed Velaz, age 20 months (N~24). Sabeluzole was administered as a mixture to standard diet in the daily dose 10 mg/kg for 10 weeks in 12 animals, the other 12 animals were fed normal diet. In the tenth week of experiment, behavioural tests were performed (open field behaviour, motor performance on rotating cilinder). All rats were then decapitated, the brains quickly removed and dissected in 4 parts (cortex, hippoeampus, hypothalamus, striatum) for biochemical analysis, using previously established biochemical markers of brain aging (Benesova et al, 1989): high-affinity choline uptake (I-IACU), concentrations of noradrenaline, dopamine, serotonin and their metabolites, lipid peroxidation, protein insolubilization. Behavioural tests indicated no difference between experimental and control group in motor performance on the rotating eilinder, but there was a higher rate of open field exploratory activity in sabeluzole treated animals. The brains of these rats exhibited significant differences in monoamine metabolism ( increased noradrenaline concentration in the hypothalamus, activation of dopamine turnover in the striatum and hypothalamus). Cholinergic neuronal activity in the hippocampus (HACU) was not changed. Lipid peroxidation - as the marker of free radical membrane damage - was markedly decreased in the cortex of sabeluzole treated rats, whereas the solubility of cortical membrane proteins did not differ between the two groups. These results suggest that 10-week sabeluzole treatment in old rats might decelerate the progress of behavioural decline and neurobiochemical deterioration in aging brain.
406 References Benesova, O., et al, 1989, Activ. Nerv. Sup. 31,231. Benesova, O., et al, 1990, Aetiv. Nerv. Sup. 32, 53. Tritsmans, L., et al, 1990, Drug Dev. Res. 20, 473.
Caroxazone: a short-acting and reversible monoamine oxidase inhibitor with therapeutic potential for Parkinson's disease
Caccia, C., Carfagna, N., Fornaretto, M.G., Cavanus, S., Mantegani, S., Roncucci R. and Fariello, R.G. CNS Department, Farmitalia Carlo Erba-Erbamont Group, Nerviano, Italy Experimental and clinical studies (Moretti et al, 1981a,b) showed that caroxazone [2-oxo-2H-1,3-benzoxazine-3(4H)acetamide] is a short-acting, reversible monoamine oxidase (MAO) inhibitor. In vitro, in rat brain mitochondria it exhibited a greater specificity towards the form B flCs0=32 and 4 /aM for MAO-A and MAO-B, respectively). Full reversibility of caroxazone MAO-inhibitory activity was confirmed directly by washings and dialysis experiments. In vivo, the decrease in dopamine (DA) and serotonin metabolite levels displayed also some inhibition of MAO-A. This effect was very short-lasting, since enzyme activity and metabolite levels returned to control values 6-9 hrs after oral high doses (50-100 mg/kg). Caroxazone did not affect blood pressure and did not potentiate the tyramine-induced increase in blood pressure even at high doses. In C57B1 mice, caroxazone prevented brain DA depletion induced by lmethyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP). The 70% reduction in striatal DA levels after MPTP was completely prevented by prior administration of caroxazone at 1 and 6 hr, at 9 hr before MPTP no protective effect was displayed due to its reversibility (ED50=5.5 mg/kg orally). In man, caroxazone was well tolerated even at high doses og 600-800 mg and its administration resulted in a dose dependent increase of urinary tryptamine excretion which quickly returned to basal value (tth=3 days) and in a MAO activity inhibition of platelet-rich plasma (t~h=l.5 days). It has been suggested (Cohen and Mytilineou, 1985) that MAO inhibitors prevent MPTP neurotoxieRy either by inhibiting the increased production of hydrogen peroxide associated with MAO-A action on dopamine and/or by preventing the oxidation of MPTP to active metabolites involved in the neurotoxicity (MAO-B). A reversible, mixed MAO inhibition could be beneficial in slowing down neurodegenerative process in Parkinson's Disease and possibly Alzheimer's Disease. Caroxazone would seem to be a suitable therapeutic candidate with interesting potential for these syndromes. References Moretli, A., Caccia, C., Calderini, G., Menozzi, M. and Amico, A., 1981a, Studies on the mechanism of Action of caroxazone, a new antidepressantdrug. Biochem. Pharmacol. 30, 2728. Moretti, A., Caecia, C., Martini, A., Bonollo, L., Amico, A., Sega, R., Nicolella, V. and Nicolis, F.B., 1981b, Effect of caroxazone, a new antidepressantdrug, on monoamineoxidases in healthy volunteers.Br. J. Clin. Pharmac. 11, 511. Cohen, G. and Mytilineou,C., 1985, Studies on the mechanismof Actionof l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). Life Sei. 35, 237.