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Eticlopride modifies the food intake by its influence on neuropeptide Y in the hypothalamus
EFFECTS OF COMBINATION NALOXONE, CYCLODOLUM AND DIPHENINUMON MPP+-INDUCED PARKINSONIAN SYNDROME
BRAIN MONOAMINES METABOLISM IN TRANSGENIC MICE EXPRESSING HIGH LEVELS OF HUMAN NEURONAL MONOAMINE OXIDASE B. E. Borroni~ J. Gottowik, A:-Cesura, P. Malherbe and M. DaPrada. Pharma Division, Preclinical Research, F. Hoffmatm-La Roche Ltd., CH4002 Basle, Switzert~md.
M.A.Atadzhanov~ A.R.Rakhimdzhonov, Centr.Resp.Lab.Dept.N eurol.Institute of Advanced Medical Studies, Parkentskaya Str, 51, 700007 Tashkent, Republic of Uzbekistan.
We have studied the metabolism of dopamine, noradtenaline and semtonin in tnmsgenic mice expressing aberrantly high level of human monoamine oxidase B (MAO-B). In these mice, the expression of human MAO-B is restricted to neurones due to the use of the rat neurone-specific enolase promoter. These mice express 4-6 time higher MAO-B activity in brain whereas the activity of MAO-A is not different from that of the non tmmgenic littermates (control mice). In contrast, the MAO-B activity in the liver of lramgenic mice was equal to that of control animals confirming neurone-specific expression. Analysis of brain monoamines in 5 weeks old transgenie mice show a 30-40% increase (p> 0.01 vs. control mice) in the basal levels of the dopamiue metabolites DOPAC and HVA whereas no changes were obscrved in the basal levels of dopamine (DA). In addition no changes were seen in the basal levds of serotonin and noradrenaline and their metabolites 5-HIAA and MOPEG, respectively. To evaluate the rate of formation of DOPAC in brain, control and transgenic mice, were treated with Tolcapone (an inhibitor of COMT) and Probeuedd (an inhibitor of the acid carrier). Under this experimental condition control mice produce 3.4+_0.1 nmoles/hour/g of brain (wet weight) of DOPAC whereas mice exl~e.sging highlevd of MAO-B produced 4.1+_0.2 nmoles/h0ur/g of tissue (p<0.01 vs. control). Thus, transgenie mice metabolise approximately 20% more DA than control animals. Since no change is seen in the DA basal level it seems likely that the increased production of DOPAC is due to enhanced DA biosynthesis, The increased rate of doparalne metabolism observed in mice expressing high level of human MAO-B is likely to translate i n a higher oxidant stress since the conversion of DA to DOPAC, catalysed by MAO, is stoichiomel:rically linked to the produelJon of hydrogen peroxide. Further experiments aimed to study the effects of such stress on dopaminergic neurones are in progress.
A single doses of all the drugs were adrriinistered i.p.48h. after intranigral injection of MPP+ when parkinsonian syndrome (PS) in rats was manifest significantly. Movement disorders and electrical activity of the brain structures were registered during 8h. after the drugs injections. Treatment with naloxone (0,5mg/kg) produced biphasic effect on rat's clocomotor activity, firstly (15-40 rain) activated (about 25%), then inhibited (l-3h). Naloxone did not produce any noticeable effect on rigidity. Locomotor stimulation effect of naloxone was correlated with a decrease of amplitude the paroxysmal activity (PA) in the caudate nuclei. Combination a half doses of cyclodolum and naloxone decreased extrapyramidal symptoms less (about 25%) then full dose of cyclodolum alone. Coadministration of cyclodolum (3mg/kg)+naloxone (0,25mg/kg) and dipheninum (10mg/kg) reduced extrapyramidal symptoms which were more marked ( about 50%) 3-4 h after the administration of drugs and followed by full suppression of the PA in the brain structures studied. The results of present study indicate that naloxone decreased but dipheninum potentiates and prolongs antiparkinsonian effect of cyclodolum in MPP+ model of PS.
CABERGOLINE REVERSAL OF MPTP-INDUCED PARKINSONISM IN MONKEYS M.A. Cervini. W Kozak, M Brughera, R.A. McArthur and R. Fariello Pharmacia SpA, CNS, Research and Development, Via Giovanni XXIII, 23,20014 Nerviano, Milan, Italy.
ETICLOPRIDE MODIFIES THE FOOD INTAKE BY ITS INFLUENCE ON NEUROPEPTIDE Y IN THE HYPOTHALAMUS. K.Kmieciak-Ko~ada, J.Pawiowski, E.Obuchowicz and Z.S.Herman Silesian University School of Medicine,Department of Clinical Pharmacology, Medyk6w Str.18, 40-752 Katowice, Poland Dopamine(DA) play a role in mediating the hedonic aspects of eating. This neurotransmitter has a dual function in eating and appears to be especially relevant, when palatable food are being consumed.There are direct evidence for antagonistic interactions between DA and neuropeptide Y (NPY) on feeding regulation in the perifornical hypothalamus (HT).Therefore the aim of the present study was to determine the effect of S(-)-Eticlopride (ET)-the selective DA 2 receptor antagonist on the concentration of NPY in the rat brain and compare with feeding behaviour.Adult ,male, Sprague Dawley rats were used.After single and 14-day administration of ET lmg/kg ip. food and body weight were registered. Then the rats were sacrificed and HT and nucleus accumbens (AN) were dissected from the brain and NPY concentration was measured by radioimmunoasay. The level of NPY was decreased in HT and AN after single injection of ET. 14 days of ET administration this effect was observed only in HT. At the same time ET decreased food intake and body weight of rats was lower in comparison With the control group. ET in dose 0.1mg/kg ip. attenuated feeding in food-deprived rats. Our results confirm that supression of spontaneous eating by ET may be partly caused by the influence on NPY neurons. Moreover hypothalamic sites are paticularly important for central regulation of food intake.
Cabergoline (CAB) is a dopamine D-2 agonist which acutely administered at the doses of 0.5 and I mg/kg sc in MPTP-treated monkeys restores motility (Carfagna et al,, 1991, Abstracts Society For Neuroscience, 21st annual meeting, New Orleans, Louisiana, 424.3). MPTP toxicity manifests itself both in humans and monkeys through a Parkinson-like syndrome of akinesia, flexed posture, rigidity, tremors, loss of vocalisation and interest in food (Langsten et al, 1983, Science, 219,979; Burns et al, 1983, Proc. Natl. Acad. Sci. U.S.A. 80: 4546). The present study was designed to evaluate the possible effects of repeated doses of CAB in reversing the MPTP-induced parkinsonian syndrome in cynomolgus monkeys. Three monkeys received repeated administrations (6-29) of CAB at different doses both subcutaneously (sc, 0.1-0.5 mg/kg) and orally (po, 0.5-2 mg/kg) 12 or 47 days after MPTP (0.35 mg/kg; i.v. x 3 days) and their behaviour was observed and scored. CAB sc and p o administered reversed the parkinsonian syndrome in the all monkeys. The minimal effective doses were 0.1 mg/kg sc and 2 mg/kg po. The effect was dose-dependent and long-lasting; higher doses inducing more intense and longer effects. Clear stimulation and moderate stereotypies without lingual diskinesia occurred only with higher dosages. Repeated treatmentswere always active and only a decrease in the duration of the effect was observed. The recovery of activity was followed by a relatively smooth wearing-off phase. In conclusion, sc and po CAB appears to be a suitable candidate for therapeutic use in parkinsonism. Moreover, CAB offers advantages over the existing treatment with I-DOPA in that the "on-off' effect and stereotypies observed with the other treatment are minimal.
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105
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BRAIN MONOAMINES METABOLISM IN TRANSGENIC MICE EXPRESSING HIGH LEVELS OF HUMAN NEURONAL MONOAMINE OXIDASE B. E. Borroni~ J. Gottowik, A:-Cesura, P. Malherbe and M. DaPrada. Pharma Division, Preclinical Research, F. Hoffmatm-La Roche Ltd., CH4002 Basle, Switzert~md.
M.A.Atadzhanov~ A.R.Rakhimdzhonov, Centr.Resp.Lab.Dept.N eurol.Institute of Advanced Medical Studies, Parkentskaya Str, 51, 700007 Tashkent, Republic of Uzbekistan.
We have studied the metabolism of dopamine, noradtenaline and semtonin in tnmsgenic mice expressing aberrantly high level of human monoamine oxidase B (MAO-B). In these mice, the expression of human MAO-B is restricted to neurones due to the use of the rat neurone-specific enolase promoter. These mice express 4-6 time higher MAO-B activity in brain whereas the activity of MAO-A is not different from that of the non tmmgenic littermates (control mice). In contrast, the MAO-B activity in the liver of lramgenic mice was equal to that of control animals confirming neurone-specific expression. Analysis of brain monoamines in 5 weeks old transgenie mice show a 30-40% increase (p> 0.01 vs. control mice) in the basal levels of the dopamiue metabolites DOPAC and HVA whereas no changes were obscrved in the basal levels of dopamine (DA). In addition no changes were seen in the basal levds of serotonin and noradrenaline and their metabolites 5-HIAA and MOPEG, respectively. To evaluate the rate of formation of DOPAC in brain, control and transgenic mice, were treated with Tolcapone (an inhibitor of COMT) and Probeuedd (an inhibitor of the acid carrier). Under this experimental condition control mice produce 3.4+_0.1 nmoles/hour/g of brain (wet weight) of DOPAC whereas mice exl~e.sging highlevd of MAO-B produced 4.1+_0.2 nmoles/h0ur/g of tissue (p<0.01 vs. control). Thus, transgenie mice metabolise approximately 20% more DA than control animals. Since no change is seen in the DA basal level it seems likely that the increased production of DOPAC is due to enhanced DA biosynthesis, The increased rate of doparalne metabolism observed in mice expressing high level of human MAO-B is likely to translate i n a higher oxidant stress since the conversion of DA to DOPAC, catalysed by MAO, is stoichiomel:rically linked to the produelJon of hydrogen peroxide. Further experiments aimed to study the effects of such stress on dopaminergic neurones are in progress.
A single doses of all the drugs were adrriinistered i.p.48h. after intranigral injection of MPP+ when parkinsonian syndrome (PS) in rats was manifest significantly. Movement disorders and electrical activity of the brain structures were registered during 8h. after the drugs injections. Treatment with naloxone (0,5mg/kg) produced biphasic effect on rat's clocomotor activity, firstly (15-40 rain) activated (about 25%), then inhibited (l-3h). Naloxone did not produce any noticeable effect on rigidity. Locomotor stimulation effect of naloxone was correlated with a decrease of amplitude the paroxysmal activity (PA) in the caudate nuclei. Combination a half doses of cyclodolum and naloxone decreased extrapyramidal symptoms less (about 25%) then full dose of cyclodolum alone. Coadministration of cyclodolum (3mg/kg)+naloxone (0,25mg/kg) and dipheninum (10mg/kg) reduced extrapyramidal symptoms which were more marked ( about 50%) 3-4 h after the administration of drugs and followed by full suppression of the PA in the brain structures studied. The results of present study indicate that naloxone decreased but dipheninum potentiates and prolongs antiparkinsonian effect of cyclodolum in MPP+ model of PS.
CABERGOLINE REVERSAL OF MPTP-INDUCED PARKINSONISM IN MONKEYS M.A. Cervini. W Kozak, M Brughera, R.A. McArthur and R. Fariello Pharmacia SpA, CNS, Research and Development, Via Giovanni XXIII, 23,20014 Nerviano, Milan, Italy.
ETICLOPRIDE MODIFIES THE FOOD INTAKE BY ITS INFLUENCE ON NEUROPEPTIDE Y IN THE HYPOTHALAMUS. K.Kmieciak-Ko~ada, J.Pawiowski, E.Obuchowicz and Z.S.Herman Silesian University School of Medicine,Department of Clinical Pharmacology, Medyk6w Str.18, 40-752 Katowice, Poland Dopamine(DA) play a role in mediating the hedonic aspects of eating. This neurotransmitter has a dual function in eating and appears to be especially relevant, when palatable food are being consumed.There are direct evidence for antagonistic interactions between DA and neuropeptide Y (NPY) on feeding regulation in the perifornical hypothalamus (HT).Therefore the aim of the present study was to determine the effect of S(-)-Eticlopride (ET)-the selective DA 2 receptor antagonist on the concentration of NPY in the rat brain and compare with feeding behaviour.Adult ,male, Sprague Dawley rats were used.After single and 14-day administration of ET lmg/kg ip. food and body weight were registered. Then the rats were sacrificed and HT and nucleus accumbens (AN) were dissected from the brain and NPY concentration was measured by radioimmunoasay. The level of NPY was decreased in HT and AN after single injection of ET. 14 days of ET administration this effect was observed only in HT. At the same time ET decreased food intake and body weight of rats was lower in comparison With the control group. ET in dose 0.1mg/kg ip. attenuated feeding in food-deprived rats. Our results confirm that supression of spontaneous eating by ET may be partly caused by the influence on NPY neurons. Moreover hypothalamic sites are paticularly important for central regulation of food intake.
Cabergoline (CAB) is a dopamine D-2 agonist which acutely administered at the doses of 0.5 and I mg/kg sc in MPTP-treated monkeys restores motility (Carfagna et al,, 1991, Abstracts Society For Neuroscience, 21st annual meeting, New Orleans, Louisiana, 424.3). MPTP toxicity manifests itself both in humans and monkeys through a Parkinson-like syndrome of akinesia, flexed posture, rigidity, tremors, loss of vocalisation and interest in food (Langsten et al, 1983, Science, 219,979; Burns et al, 1983, Proc. Natl. Acad. Sci. U.S.A. 80: 4546). The present study was designed to evaluate the possible effects of repeated doses of CAB in reversing the MPTP-induced parkinsonian syndrome in cynomolgus monkeys. Three monkeys received repeated administrations (6-29) of CAB at different doses both subcutaneously (sc, 0.1-0.5 mg/kg) and orally (po, 0.5-2 mg/kg) 12 or 47 days after MPTP (0.35 mg/kg; i.v. x 3 days) and their behaviour was observed and scored. CAB sc and p o administered reversed the parkinsonian syndrome in the all monkeys. The minimal effective doses were 0.1 mg/kg sc and 2 mg/kg po. The effect was dose-dependent and long-lasting; higher doses inducing more intense and longer effects. Clear stimulation and moderate stereotypies without lingual diskinesia occurred only with higher dosages. Repeated treatmentswere always active and only a decrease in the duration of the effect was observed. The recovery of activity was followed by a relatively smooth wearing-off phase. In conclusion, sc and po CAB appears to be a suitable candidate for therapeutic use in parkinsonism. Moreover, CAB offers advantages over the existing treatment with I-DOPA in that the "on-off' effect and stereotypies observed with the other treatment are minimal.
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105
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