RESUMEN

Discovery of the rapid antidepressant effect of ketamine has been considered one of the most important advances in major depressive disorder treatment. Several studies report a significant benefit to patients that lasts up to 19 days after treatment. However, concerns arise from the long-term use of ketamine, thus a safe and effective strategy for maintaining its antidepressant effect is still necessary. To this end, our work assessed the effects of imipramine and fluoxetine after repeated ketamine treatment in male mice. Ketamine (30 mg/kg/day for 14 days) induced an anti-immobility effect in the forced swimming (FS) paradigm, detected 1 and 3 days after treatment. Seven days after the last ketamine injection, mice received imipramine (20 mg/kg) or fluoxetine (30 mg/kg). Imipramine and fluoxetine did not change mice's immobility time, regardless of the pre-treatment (saline or ketamine). Since both drugs' anti-immobility effect was demonstrated in the classical FS test, we can assume that repeated exposure to intermittent stress inhibited the antidepressant drugs' anti-immobility effects. Moreover, pre-exposure to ketamine did not counteract stress-induced changes in mice response to antidepressants. Since exposure to forced swim and i.p. injections are stressful to rodents, each stressor's contribution to the blunted response to antidepressants was investigated. Our data demonstrated that both stressors (FS and i.p. injections) influenced the reported effect. In summary, our results showed that exposure to intermittent repeated stress inhibited the anti-immobility effect of imipramine and fluoxetine in mice and corroborated findings demonstrating that exposure to stress can blunt patients' response to antidepressants.

Asunto(s)

Antidepresivos de Segunda Generación/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Fluoxetina/administración & dosificación , Imipramina/administración & dosificación , Ketamina/administración & dosificación , Estrés Psicológico/psicología , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratones

RESUMEN

Abstract Previous pre-clinical studies demonstrated that a valepotriates enriched fraction from Valeriana glechomifolia F.G. Mey., Caprifoliaceae, was effective against lipopolysaccharide from Escherichia coli (LPS)-induced sickness behavior as well as significantly decreased the cortical expression of pro inflammatory cytokines interleukin-1β and tumor necrosis factor-α. Other studies revealed anti-inflammatory properties of V. wallichii and V. amurensis. These findings open up new perspectives for Valeriana genus pharmacology, once it has been commonly associated to sedative and anxiolytic properties. The aim of this study was to investigate the antichemotactic, antinociptive and anti-inflammatory activities of a valepotriate-enriched fraction obtained from aerial and subterranean parts of V. glechomifolia submitted to supercritical CO2 extraction. The biological activities were assessed by means of formalin test in CF1 mice and Wistar rat's leukocytes migration assay (modified Boyden chamber method). Valepotriate-enriched fraction (1, 10 and 30 mg/kg, p.o.) inhibited the nociceptive behavior in the late phase of the formalin test in a dose dependent manner. The effect of the valepotriate-enriched fraction highest dose was comparable with that of diclofenac 50 mg/kg (p.o.). Valepotriate-enriched fraction (0.1-1 µg/ml) inhibited the leukocyte migration induced by lipopolysaccharide from Escherichia coli in a concentration dependent manner. This antichemotatic effect was comparable with that of indomethacin (0.1-1 µg/ml) and better than diclofenac (1 µg/ml) effect. This study demonstrated for the first time that a valepotriate-enriched fraction obtained from V. glechomifolia display a peripheral anti-inflammatory like activity.

RESUMEN

ABSTRACT Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

Asunto(s)

Animales , Masculino , Conejos , Esquizofrenia/fisiopatología , Natación/fisiología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Ketamina/farmacología , Anestésicos Disociativos/farmacología , Esquizofrenia/inducido químicamente , Conducta Animal/fisiología , Inmovilización/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología

RESUMEN

Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

Asunto(s)

Anestésicos Disociativos/farmacología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Ketamina/farmacología , Esquizofrenia/fisiopatología , Natación/fisiología , Animales , Conducta Animal/fisiología , Inmovilización/fisiología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Esquizofrenia/inducido químicamente

RESUMEN

ABSTRACT Uliginosin B, a phloroglucinol isolated from Hypericum polyanthemum Klotzsch ex Reichardt, Hypericaceae, has antidepressant-like effect in the forced swimming test in rodents and inhibits monoamines neuronal reuptake without binding to their neuronal carriers. Studies showed the involvement of Na+,K+-ATPase brain activity in depressive disorders, as well as the dependence of neuronal monoamine transport from Na+ gradient generated by Na+,K+-ATPase. This study aimed at evaluating the effect of uliginosin B on Na+,K+-ATPase activity in mice cerebral cortex and hippocampus (1 and 3 h after the last administration) as well as the influence of veratrine, a Na+ channel opener, on the antidepressant-like effect of uliginosin B. Mice were treated (p.o.) with uliginosin B single (10 mg/kg) or repeated doses (10 mg/kg/day, 3 days). Acute administration reduced the immobility in the forced swimming test and tail suspension test and increased Na+,K+-ATPase activity in cerebral cortex 1 h after treating, whereas the repeated treatment induced the antidepressant-like effect and increased the Na+,K+-ATPase activity at both times evaluated. None treatment affected the hippocampus enzyme activity. Veratrine pretreatment prevented uliginosin B antidepressant-like effect in the forced swimming test, suggesting the involvement of Na+ balance regulation on this effect. Altogether, these data indicate that uliginosin B reduces the monoamine uptake by altering Na+ gradient.

RESUMEN

Three dimeric acylphloroglucinols, austrobrasilol A, austrobrasilol B and isoaustrobrasilol B were isolated from the flowers of Hypericum austrobrasiliense (Hypericaceae, section Trigynobrathys). Their structures were elucidated using mass spectrometry and NMR experiments (1D and 2D), and by comparison with previously reported data for other dimeric acylphloroglucinols isolated from Hypericum and Elaphoglossum genera. The three compounds were orally administered in mice at equimolar doses to uliginosin B (15mg/kg, p.o.) displaying antinociceptive activity in the hot-plate test. The compounds did not induce motor impairment in the rotarod apparatus.

Asunto(s)

Analgésicos/aislamiento & purificación , Analgésicos/farmacología , Hypericum/química , Floroglucinol/análogos & derivados , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Analgésicos/química , Animales , Brasil , Masculino , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Resonancia Magnética Nuclear Biomolecular , Floroglucinol/química

RESUMEN

Previous studies on the N-phenylpiperazine derivative LASSBio-579 have suggested that LASSBio-579 has an atypical antipsychotic profile. It binds to D2, D4 and 5-HT1A receptors and is effective in animal models of schizophrenia symptoms (prepulse inhibition disruption, apomorphine-induced climbing and amphetamine-induced stereotypy). In the current study, we evaluated the effect of LASSBio-579, clozapine (atypical antipsychotic) and haloperidol (typical antipsychotic) in the novel object recognition task, a recognition memory model with translational value. Haloperidol (0.01 mg/kg, orally) impaired the ability of the animals (CF1 mice) to recognize the novel object on short-term and long-term memory tasks, whereas LASSBio-579 (5 mg/kg, orally) and clozapine (1 mg/kg, orally) did not. In another set of experiments, animals previously treated with ketamine (10 mg/kg, intraperitoneally) or vehicle (saline 1 ml/100 g, intraperitoneally) received LASSBio-579, clozapine or haloperidol at different time-points: 1 h before training (encoding/consolidation); immediately after training (consolidation); or 1 h before long-term memory testing (retrieval). LASSBio-579 and clozapine protected against the long-term memory impairment induced by ketamine when administered at the stages of encoding, consolidation and retrieval of memory. These findings point to the potential of LASSBio-579 for treating cognitive symptoms of schizophrenia and other disorders.

Asunto(s)

Antipsicóticos/farmacología , Piperazinas/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Animales , Clozapina/farmacología , Modelos Animales de Enfermedad , Haloperidol/farmacología , Ketamina/farmacología , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Esquizofrenia/fisiopatología , Factores de Tiempo

RESUMEN

OBJECTIVES: Combinations of different classes of antidepressants (including herbal adjuvants) have been used as an alternative means of achieving better results in the treatment of depressed patients. However, studies characterizing the interactions between herbal adjuvants and antidepressants are lacking. This study is the first to investigate the interaction between diene valepotriates (VAL) from Valeriana glechomifolia, a species with antidepressant-like effects, and imipramine (IMI), desipramine (DESI) and bupropion (BUP). The interactions were assessed via isobolographic analyses, which represent a tool for evaluating interactions between drugs. METHODS: The interaction between VAL and each antidepressant was evaluated in mice given concurrent oral administration of each drug with fixed ED50 ratios and subjected to a forced swimming test (FST). Spontaneous locomotion was measured in the open field test. KEY FINDINGS: The drug combinations produced a dose-dependent anti-immobility effect in the FST without altering mouse locomotor activity. Isobolographic analysis revealed that VAL resulted in synergistic interactions in combination with each of the antidepressants tested. CONCLUSION: The synergistic interactions between VAL and IMI, DESI and BUP highlight the potential for VAL to serve as adjuvants to antidepressant drugs and suggest that VAL does not directly target the same sites on neuronal transporters as the antidepressants.

Asunto(s)

Antidepresivos/farmacología , Iridoides/farmacología , Locomoción/efectos de los fármacos , Valeriana/química , Animales , Encéfalo/efectos de los fármacos , Bupropión/farmacología , Sinergismo Farmacológico , Imipramina/farmacología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Natación/fisiología

RESUMEN

Diene valepotriates obtained from Valeriana glechomifolia present antidepressant-like activity, mediated by dopaminergic and noradrenergic neurotransmissions. Also, previous studies have shown inhibitory activity of diene valepotriates towards Na(+)/K(+)-ATPase from the rat brain in vitro. Nevertheless, in vivo studies regarding the action of diene valepotriates on this enzyme are still lacking. Considering that Na(+)/K(+)-ATPase cerebral activity is involved in depressive disorders, the aim of this study was to investigate the effects of acute (5 mg/kg, p. o.) and repeated (5 mg/kg, p. o., once a day for three days) diene valepotriate administration on Na(+)/K(+)-ATPase activity in the cortex and hippocampus of mice submitted or not submitted to the forced swimming test. In addition, the protein expression of Na(+)/K(+)-ATPase α1, α2, and α3 isoforms in the cortex of mice repeatedly treated with diene valepotriates (and submitted or not submitted to the forced swimming test) was investigated. Diene valepotriates significantly decreased mice immobility time in the forced swimming test when compared to the control group. Only the animals repeatedly treated with diene valepotriates presented increased Na(+)/K(+)-ATPase activity in the cerebral cortex, and the exposure to the forced swimming test counteracted the effects of the diene valepotriates. No alterations in the hippocampal Na(+)/K(+)-ATPase activity were observed. Repeated diene valepotriate administration increased the cortical content of the α2 isoform, but the α3 isoform protein expression was augmented only in mice repeatedly treated with diene valepotriates and forced to swim. Mice treated with the vehicle and submitted to the forced swimming test also presented an increase in the content of the α2 isoform, but no alterations in Na(+)/K(+)-ATPase activity. These results suggest that cortical Na(+)/K(+)-ATPase may represent a molecular target of the diene valepotriates in vivo and long-term regulatory mechanisms are involved in this effect. Also, the forced swimming test per se influences the protein expression of Na(+)/K(+)-ATPase isoforms and counteracts the effects of the diene valepotriates on cortical Na(+)/K(+)-ATPase.

Asunto(s)

Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Iridoides/farmacología , Actividad Motora/efectos de los fármacos , Extractos Vegetales/farmacología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Valeriana/química , Animales , Antidepresivos/uso terapéutico , Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Iridoides/uso terapéutico , Masculino , Ratones , Fitoterapia , Extractos Vegetales/uso terapéutico , Isoformas de Proteínas , Estrés Psicológico/tratamiento farmacológico , Natación

RESUMEN

Uliginosin B is a natural phloroglucinol derivative, obtained from Hypericum species native to South America. Previous studies have shown that uliginosin B presents antidepressant-like and antinociceptive effects. Although its mechanism of action is still not completely elucidated, it is known that it involves the activation of monoaminergic neurotransmission. The aim of the current study was to further investigate the antinociceptive mechanism of action of uliginosin B by combining it with different drugs used for treating pain in clinical practice. The intraperitoneal administration of uliginosin B, morphine, amitriptyline and clonidine, alone or in mixture, produced a dose-dependent antinociceptive effect in the hot-plate assay in mice. The effect of the mixtures of drugs was studied using an adapted isobologram analysis at the effect level of 50% of the maximal effect observed. The analysis showed that the interactions between uliginosin B and morphine was synergistic, while the interactions between uliginosin B and amitriptyline or clonidine were additive. These findings point to uliginosin B as a potential adjuvant for pain pharmacotherapy, especially for opioid analgesia.

Asunto(s)

Analgésicos/farmacología , Floroglucinol/análogos & derivados , Amitriptilina/farmacología , Animales , Clonidina/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Hypericum/química , Masculino , Ratones , Morfina/farmacología , Dolor/tratamiento farmacológico , Floroglucinol/farmacología , Componentes Aéreos de las Plantas/química

RESUMEN

A new dimeric acylphloroglucinol derivative, andinin A (1), was isolated from the underground plant parts of Hypericum andinum, along with three known dimeric acylphloroglucinols, uliginosin A (2), uliginosin B (3), and isouliginosin B (4). The structure of 1 was elucidated using 1D and 2D NMR and MS experiments and by comparison with previously reported data for Hypericum dimeric acylphloroglucinols. Andinin A (1) displayed antidepressant-like activity in a mouse forced-swimming test when administered orally at doses of 3, 10, and 30 mg/kg.

Asunto(s)

Antidepresivos , Hypericum/química , Floroglucinol , Administración Oral , Animales , Antidepresivos/química , Antidepresivos/aislamiento & purificación , Antidepresivos/farmacología , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Perú , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología

RESUMEN

OBJECTIVE: Investigate the involvement of monoaminergic and glutamatergic systems on the antinociceptive and ataxic effects of uliginosin B, which we have already demonstrated to be a promising molecular scaffold to develop new analgesic drugs. METHODS: Uliginosin B was obtained from hexane extract of aerial parts of Hypericum polyanthemum by chromatographic methods. Uliginosin B antinociceptive and motor coordination effects were evaluated in mice by using hot-plate (15 and 90 mg/kg, i.p.) and rotarod (90 mg/kg, i.p.) tests, respectively. The mechanism of action was investigated through pretreatments with prazosin 1 mg/kg intraperitoneal (α1 receptor antagonist), yohimbine 5 mg/kg intraperitoneal (α2 receptor antagonist), pCPA 300 mg/kg intraperitoneal (serotonin synthesis inhibitor) and MK-801 0.25 mg/kg intraperitoneal (N-methyl-D-aspartic acid receptor antagonist). KEY FINDINGS: The antinociceptive effect of uliginosin B (15 and 90 mg/kg, i.p.) was reduced significantly by pCPA and MK-801. Prazosin and yohimbine improved the antinociceptive effect of the highest dose (90 mg/kg, i.p.) of uliginosin B only. The ataxic effect of uliginosin B (90 mg/kg, i.p.) was completely prevented by pretreatment with pCPA or MK-801, but it was unaffected by pretreatment with prazosin or yohimbine. CONCLUSION: These data confirm the contribution of monoaminergic neurotransmission as well as provide the first evidence of glutamatergic neurotransmission contribution to the uliginosin B effects.

Asunto(s)

Analgésicos/farmacología , Conducta Animal/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Floroglucinol/análogos & derivados , Analgésicos/aislamiento & purificación , Analgésicos/uso terapéutico , Animales , Monoaminas Biogénicas/metabolismo , Ácido Glutámico/metabolismo , Hypericum/química , Masculino , Ratones Endogámicos , Dolor/metabolismo , Dolor/psicología , Dimensión del Dolor , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Floroglucinol/uso terapéutico , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Transmisión Sináptica/efectos de los fármacos

RESUMEN

Ethnobotanical data can be an important tool in the search for new drugs. The Brazilian Health Surveillance Agency accepts the registration of herbal medicines based on ethnopharmacological and ethnobotanical studies. With the purpose of increasing the knowledge of potentially useful plants for the treatment of painful conditions, we analyzed the ethnobotanical studies carried out in Rio Grande do Sul state (RS-Southern Brazil); we had access to nineteen studies.To our knowledge, this is the first compilation of ethnobotanical studies that focus on pain relief carried out in RS. The species native to RS cited in at least nine (about 50%) of these studies were selected. The search retrieved 28 native species cited as used to alleviate painful conditions, which are distributed in eighteen botanical families, being Asteraceae the most mentioned. The species more frequently cited for pain relief were Achyrocline satureioides, Baccharis articulata, Baccharis crispa, Lepidium didymum, Eugenia uniflora and Maytenus ilicifolia. The only species not reported in any pre-clinical study associated with pain relief was B. articulata. Among the six species cited, no studies on clinical efficacy were found. In conclusion, the folk use of native plants with therapeutic purposes is widespread in RS State (Brazil), being pain relief an important property.

RESUMEN

In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT(2A) receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3-10-fold for the 5-HT(2A) receptor, with no relevant change in the affinity for the D2-like and 5-HT(1A) receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5-HT(2A) receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound.

Asunto(s)

Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Diseño de Fármacos , Piperazinas/química , Piperazinas/síntesis química , Piperazinas/farmacología , Animales , Antipsicóticos/química , Antipsicóticos/uso terapéutico , Conducta Animal/efectos de los fármacos , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Locomoción/efectos de los fármacos , Masculino , Ratones , Piperazinas/uso terapéutico , Receptor de Serotonina 5-HT2A/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología

RESUMEN

Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1-(4-chlorophenyl)-1H-4pyrazolylmethyl] phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3).

Asunto(s)

Antipsicóticos/farmacología , Plomo/química , Compuestos Organometálicos/farmacología , Piperazinas/química , Animales , Antipsicóticos/química , Antipsicóticos/metabolismo , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Masculino , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Piperazinas/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D4/antagonistas & inhibidores , Relación Estructura-Actividad

RESUMEN

Previous behavioral and receptor binding studies on N-phenylpiperazine derivatives by our group indicated that LASSBio-579, LASSBio-580 and LASSBio-581 could be potential antipsychotic lead compounds. The present study identified LASSBio-579 as the most promising among the three compounds, since it was the only one that inhibited apomorphine-induced climbing (5 mg/kg p.o.) and apomorphine-induced hypothermia (15 mg/kg p.o.). Furthermore, LASSBio-579 (0.5 mg/kg p.o.) was effective in the ketamine-induced hyperlocomotion test and prevented the prepulse inhibition deficits induced by apomorphine, DOI and ketamine with different potencies (1 mg/kg, 0.5 mg/kg and 5 mg/kg p.o., respectively). LASSBio-579 also induced a motor impairment, catalepsy and a mild sedative effect but only at doses 3-120 times higher than those with antipsychotic-like effects. In addition, LASSBio-579 (0.5 and 1 mg/kg p.o.) reversed the catalepsy induced by WAY 100,635, corroborating its action on both dopaminergic and serotonergic neurotransmission and pointing to the contribution of 5-HT(1A) receptor activation to its pharmacological profile. Moreover, co-administration of sub-effective doses of LASSBio-579 with sub-effective doses of clozapine or haloperidol prevented the apomorphine-induced climbing without induction of catalepsy. In summary, our results characterize LASSBio-579 as a multi-target ligand active in pharmacological animal models of schizophrenia, confirming that this compound could be included in development programs aiming at a new drug for treating schizophrenia.

Asunto(s)

Antipsicóticos/uso terapéutico , Piperazinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/etiología , Estimulación Acústica/efectos adversos , Análisis de Varianza , Animales , Antipsicóticos/farmacología , Apomorfina/toxicidad , Barbitúricos/farmacología , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Agonistas de Dopamina/toxicidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Hipotermia/inducido químicamente , Ketamina/toxicidad , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Piperazinas/farmacología , Psicoacústica , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/fisiopatología , Sueño/efectos de los fármacos

RESUMEN

The aim of the present work was to evaluate the antidepressant like-effect and plasma concentration of Sertraline (SRT) using an inclusion complex (IC) with ß-cyclodextrin (ßCD) in mice. This supramolecular system was prepared using two different molar ratios at 1:1 and 1:2 SRT:ßCD and both were characterized to assess the drug inclusion into the host cavity. Based on the X-ray powder diffraction, Fourier transform infrared spectroscopy and thermal analysis the interaction between host and guest molecules could be suggested. This result indicates that the freeze drying process was efficient to prepare the ICs, when these are compared with the physical mixtures. By comparing the solid state results of 1:1 and 1:2 ICs no significant chemical or structural changes were identified between these systems. However, in vivo experiments indicated that the host-guest ratio was able to modify the SRT activity. Mice treated with both ICs (20 mg kg(-1), p.o.) have shown lower immobility time in the tail suspension test in comparison with mice treated with free SRT (20 mg kg(-1), p.o.). Mice spontaneous locomotor activity was not affected by any treatment. Higher SRT plasma concentration was determined after 30 min of treatment with 1:1 IC in comparison with free SRT, demonstrating the IC greater drug transport efficacy.

Asunto(s)

Antidepresivos/farmacología , Sertralina/farmacología , beta-Ciclodextrinas/farmacología , Animales , Antidepresivos/sangre , Antidepresivos/química , Suspensión Trasera , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Difracción de Polvo , Sertralina/sangre , Sertralina/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X , beta-Ciclodextrinas/química

RESUMEN

Nine new terpenylated acylphloroglucinols, crassipins A-I, were isolated from the rhizomes and roots of the fern Elaphoglossum crassipes, and their structures were elucidated by analysis of spectroscopic data and chemical derivatization. The absolute configurations of some of the compounds were established by CD and VCD in combination with a quantum mechanical method. Crassipin A (1), the major acylphloroglucinol of the Et(2)O extract of E. crassipes, as well as its peracetylated derivative (8), displayed antidepressant-like activity in a mouse forced-swimming test when administered orally at a dose of 15 mg/kg.

Asunto(s)

Antidepresivos , Dryopteridaceae/química , Floroglucinol , Administración Oral , Animales , Antidepresivos/química , Antidepresivos/aislamiento & purificación , Antidepresivos/farmacología , Argentina , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Raíces de Plantas/química , Rizoma/química , Natación

RESUMEN

Previous studies have shown that uliginosin B inhibits dopamine reuptake in rat brain. This compound occurs in Hypericum polyanthemum and H. caprifoliatum for which was reported to have antinociceptive effect sensitive to naloxone. The aim of this study was to assess the antinociceptive effect of uliginosin B and to evaluate the involvement of opioid and dopaminergic receptors activation. Uliginosin B presented antinociceptive effect in hot-plate and abdominal writhing tests, in mice, at doses that did not impair the motor coordination (15 mg/kg, i.p.). Uliginosin B in high dose (90 mg/kg, i.p.) presented ataxic effect in the rotarod apparatus. These effects seem to be mediated by distinct receptors since the effect on the hot-plate was completely abolished by naloxone and sulpiride, but it was unaffected by SCH 23390. On the other hand, the motor impairment induced by uliginosin B was completely prevented by naloxone and partially prevented by sulpiride and SCH 23390. However, the receptors' activation appears to be indirect since uliginosin B did not bind to opioid and dopaminergic receptors. Thus, uliginosin B effects probably are due to its ability to inhibit monoamine reuptake with consequent activation of dopamine receptors and indirect stimulation of opioid system.

Asunto(s)

Analgésicos/farmacología , Floroglucinol/análogos & derivados , Receptores Dopaminérgicos/metabolismo , Receptores Opioides/metabolismo , Analgésicos/antagonistas & inhibidores , Animales , Benzazepinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Antagonistas de Dopamina/farmacología , Interacciones Farmacológicas , Masculino , Ratones , Ratones Endogámicos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Dimensión del Dolor/estadística & datos numéricos , Floroglucinol/antagonistas & inhibidores , Floroglucinol/farmacología , Ensayo de Unión Radioligante/métodos , Ratas , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante/estadística & datos numéricos , Sulpirida/farmacología

RESUMEN

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 µg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC50 = 90 ± 38 nM), serotonin (IC50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

Asunto(s)

Antidepresivos/farmacología , Hypericum/química , Floroglucinol/análogos & derivados , Animales , Antidepresivos/aislamiento & purificación , Benzazepinas/farmacología , Monoaminas Biogénicas/metabolismo , Bupropión/farmacología , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/psicología , Inhibidores Enzimáticos/farmacología , Fenclonina/farmacología , Fluoxetina/farmacología , Imipramina/farmacología , Pérdida de Tono Postural/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Floroglucinol/antagonistas & inhibidores , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Prazosina/farmacología , Ratas , Ratas Wistar , Receptores de Catecolaminas/antagonistas & inhibidores , Sulpirida , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Yohimbina/farmacología