Involvement of the monoamine system in antidepressant-like properties of 4-(1-phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester (original) (raw)
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Antidepressant-like effects of piperine and its derivative, antiepilepsirine
Journal of Asian Natural Products Research, 2007
In the present study, antidepressant-like effects of piperine (PIP) and its derivative, antiepilepsirine (AES), were investigated in two depressive models: forced swimming test (FST) and tail suspension test (TST). To further explore the mechanisms underlying their antidepressant-like activities, the brain monoamine levels and monoamine oxidase A and B (MAO-A and MAO-B) activities were also determined. The research results for the first time indicated that after two weeks of chronic administration, PIP and AES at doses of 10-20 mg/kg significantly reduced the duration of immobility in both FST and TST, without accompanying changes in locomotor activity in the open-field test. But at the dose of 80 mg/kg, the antidepressant activity of both PIP and AES returned to the control level in the TST and FST. In the monoamine assay, chronic AES administration significantly elevated the dopamine level in striatum, hypothalamus and hippocampus, and also increased the serotonin level in the hypothalamus and hippocampus. In contrast, chronic treatment of PIP only enhanced the serotonin level in the hypothalamus and hippocampus but did not influence the dopamine level. Moreover, both PIP and AES showed no effects on level of noradrenaline in these brain regions. The MAO activity assay also indicated that PIP and AES showed a minor MAO inhibitory activity. In the present study, we demonstrated that the antidepressant-like effects of PIP and AES might depend on the augmentation of the neurotransmitter synthesis or the reduction of the neurotransmitter reuptake. Antidepressant properties of PIP were supposed to be mediated via the regulation of serotonergic system, whereas the mechanisms of antidepressant action of AES might be due to its dual regulation of both serotonergic and dopaminergic systems.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2018
The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-...
Drug Development Research, 1992
BW 13701187 is a potent, reversible, selective inhibitor of rat and human brain MAO-A with a competitive mechanism of action. The E D , , of BW 13701187 for inhibition of MAO-A in rat brain is 8 mg/kg after oral administration, and the duration of action exceeds 7 hr. The ED, , dose for inhibition of MAO-A (20 mg/kg) elevates NE, DA, and 5-HT levels in brains of rats without significantly potentiating the blood pressure effects of a 15 rng/kg oral dose of tyramine. This dose of tyramine, extrapolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO-B has been observed with BW 13701187 either in vitro or ex vivo. BW 13701187 was effective in the 5-hydroxytryptophan potentiation test over the dose range that produced MAO-A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has positive effects on abnormal social behavior produced by early social deprivation in the rhesus monkey. BW 13701187 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological effects on various isolated tissue preparations and did not cause changes in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressants. An acute
Progress in Neuro- …, 2008
Our previous study described the synthesis of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,Ndimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d] cycloheptane-5-one (ADDCH1), and 1,2,3,4,8,9-hexahydro-dibenzocycloheptane[4,4a,5-ef]1,4diazepin (ADDCH2), and the characterization of their antidepressant-like effect in the forced swimming test in mice. This study investigated the involvement of monoaminergic pathways in the antidepressant-like effect of these compounds in mice evaluated in the tail suspension test (TST), another animal model to screen antidepressant drugs. Our results show that the immobility time in the TSTwas significantly reduced by ADDCH1 (15 to 50 mg/kg, i.p.) or ADDCH2 (30 and 50 mg/kg, i.p.). The antidepressant-like effect of ADDCH1 (30 mg/kg, i.p.) in the TST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p.), a non-selective serotonin receptor antagonist, p-chlorophenylalanine methylester (pCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis, prazosin (62.5 μg/kg, i.p.), an α 1-adrenoceptor antagonist, or yohimbine (1 mg/kg, i.p.), an α 2-adrenoceptor antagonist. In contrast, the antidepressant-like effect of ADDCH2 was antagonized only by yohimbine (1 mg/kg) or haloperidol (50 μg/kg, i.p.), a dopamine D 2 /D 3 /D 4 receptor antagonist, and was not affected by methysergide, pCPA or prazosin. Altogether, the present results strongly suggest the differential involvement of monoaminergic systems, serotonin/noradrenaline (ADDCH1) and noradrenaline/dopamine (ADDCH2) pathways, respectively, in the antidepressant-like effect of dibenzosuberone compounds.
Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers
Neuro endocrinology letters
OBJECTIVE: Monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters, has an important role in the brain development and function, and MAO inhibitors have a range of potential therapeutic uses. We investigated systematically in vitro effects of pharmacologically different antidepressants and mood stabilizers on MAO activity. Methods: Effects of drugs on the activity of MAO were measured in crude mitochondrial fraction isolated from cortex of pig brain, when radiolabeled serotonin (for MAO-A) or phenylethylamine (for MAO-B) was used as substrate. The several antidepressants and mood stabilizers were compared with effects of well known MAO inhibitors such as moclobemide, iproniazid, pargyline, and clorgyline. Results: In general, the effect of tested drugs was found to be inhibitory. The half maximal inhibitory concentration, parameters of enzyme kinetic, and mechanism of inhibition were determined. MAO-A was inhibited by the following drugs: pargyl...
Our previous study described the synthesis of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d] cycloheptane-5-one (ADDCH1), and 1,2,3,4,8,9-hexahydro-dibenzocycloheptane[4,4a,5-ef]1,4-diazepin (ADDCH2), and the characterization of their antidepressant-like effect in the forced swimming test in mice. This study investigated the involvement of monoaminergic pathways in the antidepressant-like effect of these compounds in mice evaluated in the tail suspension test (TST), another animal model to screen antidepressant drugs. Our results show that the immobility time in the TSTwas significantly reduced by ADDCH1 (15 to 50 mg/kg, i.p.) or ADDCH2 (30 and 50 mg/kg, i.p.). The antidepressant-like effect of ADDCH1 (30 mg/kg, i.p.) in the TST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p.), a non-selective serotonin receptor antagonist, p-chlorophenylalanine methylester (pCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis, prazosin (62.5 μg/kg, i.p.), an α 1-adrenoceptor antagonist, or yohimbine (1 mg/kg, i.p.), an α 2-adrenoceptor antagonist. In contrast, the antidepressant-like effect of ADDCH2 was antagonized only by yohimbine (1 mg/kg) or haloperidol (50 μg/kg, i.p.), a dopamine D 2 /D 3 /D 4 receptor antagonist, and was not affected by methysergide, pCPA or prazosin. Altogether, the present results strongly suggest the differential involvement of monoaminergic systems, serotonin/noradrenaline (ADDCH1) and noradrenaline/dopamine (ADDCH2) pathways, respectively, in the antidepressant-like effect of dibenzosuberone compounds.
Monoamine involvement in the antidepressant-like effect induced by P2 blockade
Brain Research, 2017
Depression is a common mental disorder that affects millions of individuals worldwide. Available monoaminergic antidepressants are far from ideal since they show delayed onset of action and are ineffective in approximately 40% of patients, thus indicating the need of new and more effective drugs. ATP signaling through P2 receptors seems to play an important role in neuropathological mechanisms involved in depression, since their pharmacological or genetic inactivation induce antidepressant-like effects in the forced swimming test (FST). However, the mechanisms involved in these effects are not completely understood. The present work investigated monoamine involvement in the antidepressantlike effect induced by non-specific P2 receptor antagonist (PPADS) administration. First, the effects of combining sub-effective doses of PPADS with sub-effective doses of fluoxetine (FLX, selective serotonin reuptake inhibitor) or reboxetine (RBX, selective noradrenaline reuptake inhibitor) were investigated in mice submitted to FST. Significant antidepressant-like effect was observed when subeffective doses of PPADS was combined with subeffective doses of either FLX or RBX, with no significant locomotor changes. Next, the effects of depleting serotonin and noradrenaline levels, by means of PCPA (p-Chlorophenylalanine) or DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) pretreatment, respectively, was investigated. Both, PCPA and DSP-4 pretreatment partially attenuated PPADS-induced effects in FST, without inducing relevant locomotor changes. Our results suggest that the antidepressant-like effect of PPADS involves modulation of serotonin and noradrenaline levels in the brain.
Preclinical Evaluation of Antidepressant Activity of New Monoamine Oxidase Inhibitors in Rodents
2016
Introduction: Monoamine Oxidase Inhibitors (MAO-I) are the only antidepressants that increase levels of all three neurotransmitters implicated in depression-Serotonin, Dopamine and Norepinephrine. But, they have unfavorable side effects. Attempts were made to synthesize new MAO-Is with similar activity but better tolerability- SBK series. Materials and Methods: The study was conducted in two phases- Screening and Evaluation. In the screening phase, eight SBK Molecules (SBK1-8) were assessed for their antidepressant potential using Tail Suspension Test (TST) in mice. Four molecules out of eight-SBK4, SBK5, SBK7, SBK8-were screened and subjected to evaluation phase using various behavioral tests- Forced Swim Test (FST) in mice, Elevated Plus Maze (EPM) in rats and Unpredictable Chronic Mild Stress (UCMS) model followed by Sucrose Preference Test (SPT) in rats. Statistical analysis was done using Graph Pad Prism 5; p
Behavioural Brain Research, 2003
Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of cAMP-response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these have not been established. In the present study, chronic administration of rolipram produced antidepressant-and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, three weeks following the end of MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB, with its antidepressant-and anxiolytic-like effects resumed. Overall, the present results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: