RESUMO
Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.
Assuntos
Benzofuranos , Privação do Sono , Animais , Masculino , Camundongos , Privação do Sono/tratamento farmacológico , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a ß-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.
Assuntos
Antidepressivos , Benzamidas , Animais , Antidepressivos/farmacologia , Antidepressivos/farmacocinética , Benzamidas/farmacologia , Benzamidas/farmacocinética , Camundongos , Masculino , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacocinética , Dopamina/metabolismo , Elevação dos Membros Posteriores , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/farmacocinética , Compostos Organosselênicos/químicaRESUMO
RATIONALE: Major Depressive Disorder (MDD) significantly impairs the quality of life for those affected. While the exact causes of MDD are not fully understood, the deficit of monoamines, especially serotonin and noradrenaline, is widely accepted. Resistance to long-term treatments and adverse effects are often observed, highlighting the need for new pharmacological therapies. Synthetic organic compounds containing selenium have exhibited pharmacological properties, including potential antidepressant effects. OBJECTIVE: To evaluate the antidepressant-like effect of N-(3-((3-(trifluoromethyl)phenyl)selenyl)prop-2-yn-1-yl) benzamide (CF3SePB) in mice and the involvement of the serotonergic and noradrenergic systems. METHODS: Male Swiss mice were treated with CF3SePB (1-50 mg/kg, i.g.) and 30 min later the forced swimming test (FST) or tail suspension test (TST) was performed. To investigate the involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of CF3SePB, mice were pre-treated with p-CPA (a 5-HT depletor, 100 mg/kg, i.p.) or the receptor antagonists WAY100635 (0.1 mg/kg, s.c., a 5-HT1A receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT2A/2C receptor antagonist), ondansetron (1 mg/kg, i.p., a 5-HT3 receptor antagonist), GR110838 (0.1 mg/kg, i.p., a 5-HT4 receptor antagonist), prazosin (1 mg/kg, i.p., an α1-adrenergic receptor antagonist), yohimbine (1 mg/kg, i.p., an α2-adrenergic receptor antagonist) and propranolol (2 mg/kg, i.p., a non-selective beta-adrenergic receptor antagonist) at specific times before CF3SePB (50 mg/kg, i.g.), and after 30 min of CF3SePB administration the FST was performed. RESULTS: CF3SePB showed an antidepressant-like effect in both FST and TST and this effect was related to the modulation of the serotonergic system, specially the 5-HT1A and 5-HT3 receptors. None of the noradrenergic antagonists prevented the antidepressant-like effect of CF3SePB. The compound exhibited a low potential for inducing acute toxicity in adult female Swiss mice. CONCLUSION: This study pointed a new compound with antidepressant-like effect, and it could be considered for the development of new antidepressants.
Assuntos
Antidepressivos , Benzamidas , Relação Dose-Resposta a Droga , Animais , Masculino , Camundongos , Antidepressivos/farmacologia , Benzamidas/farmacologia , Natação , Compostos Organosselênicos/farmacologia , Serotonina/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Elevação dos Membros PosterioresRESUMO
1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.
Assuntos
Antidepressivos , Dopamina , Monoaminoxidase , Compostos Organosselênicos , Animais , Masculino , Camundongos , Antidepressivos/farmacologia , Compostos Organosselênicos/farmacologia , Monoaminoxidase/metabolismo , Monoaminoxidase/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Natação , Norepinefrina/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/metabolismo , Atividade Motora/efeitos dos fármacosRESUMO
Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D2/D3 receptor antagonist, 5 mg/kg), SCH-23390 (D1 receptor antagonist, 0.05 mg/kg), prazosin (α1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α2-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective ß-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D1, α2 and ß-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.
Assuntos
Propranolol , Qualidade de Vida , Camundongos , Animais , Propranolol/farmacologia , Propranolol/uso terapêutico , Analgésicos/toxicidade , Dor/tratamento farmacológico , Norepinefrina , Ioimbina/toxicidade , Ioimbina/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Dopamina , Sulpirida , Receptores Adrenérgicos alfa 2RESUMO
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive molecules produced naturally by the body and by external factors. When these species are generated in excessive amounts, they can lead to oxidative stress, which in turn can cause cellular and tissue damage. This damage is known to contribute to the aging process and is associated with age-related conditions, including cardiovascular and neurodegenerative diseases. In recent years, there has been an increased interest in the development of compounds with antioxidant potential to assist in the treatment of disorders related to oxidative stress. In this way, compounds containing sulfur (S) and/or selenium (Se) have been considered promising due to the relevant role of these elements in the biosynthesis of antioxidant enzymes and essential proteins with physiological functions. In this context, studies involving heterocyclic nuclei have significantly increased, notably highlighting the indolizine nucleus, given that compounds containing this nucleus have been demonstrating considerable pharmacological properties. Thus, the objective of this research was to evaluate the in vitro antioxidant activity of eight S- and Se-derivatives containing indolizine nucleus and different substituents. The in vitro assays 1,1-diphenyl-2-picryl-hydrazil (DPPH) scavenger activity, ferric ion (Fe3+) reducing antioxidant power (FRAP), thiobarbituric acid reactive species (TBARS), and protein carbonylation (PC) were used to access the antioxidant profile of the compounds. Our findings demonstrated that all the compounds showed FRAP activity and reduced the levels of TBARS and PC in mouse brains homogenates. Some compounds were also capable of acting as DPPH scavengers. In conclusion, the present study demonstrated that eight novel organochalcogen compounds exhibit antioxidant activity.
Assuntos
Antioxidantes , Selênio , Camundongos , Animais , Antioxidantes/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Estresse Oxidativo , Selênio/química , Espécies Reativas de OxigênioRESUMO
The serotonin type 4 receptor (5-HT4R)shows promise as a target for treating major depressive disorder (MDD). Studies have demonstrated that 5-HT4R agonists have a faster antidepressant-like effect compared to conventional medications. Developing drugs that modulate this receptor could lead to faster and more effective MDD treatments. The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB) induces an antidepressant-like effect in mice. The present study explored if the 5-HT4R mediates SePB's antidepressant effect. For this, male Swiss mice were treated with GR113808 (0.1 mg/kg, intraperitoneally - i.p.), a 5-HT4R antagonist, and SePB (10 mg/kg, intragastrically - i.g), and then subjected to the tail-suspension test (TST) and open-field test (OFT). In silico tests were conducted to analyze SePB's binding affinity to the 5-HT4R and identify participating amino acid residues. The administration of GR113808 blocked the antidepressant-like effect of SePB in the TST without changing locomotor activity in the OFT. Moreover, SePB exhibited a high binding affinity between the 5-HT4R (-7.9 kcal/mol) and the amino acid residues Leu298, Asp100, Thr97, Arg96, Glu80, Leu81, Cys184, Val185, and Phe186 seem to be important for this interaction. The involvement of the 5-HT4R in the antidepressant-like effect of SePB suggests potential for novel therapies in MDD.
Assuntos
Transtorno Depressivo Maior , Indóis , Serotonina , Sulfonamidas , Camundongos , Masculino , Animais , Serotonina/metabolismo , Antidepressivos/uso terapêutico , Aminoácidos , Benzamidas/farmacologia , Depressão/metabolismo , Elevação dos Membros PosterioresRESUMO
Anxiety disorders, characterized by high prevalence rates, cause psychiatric disabilities and are related to impairments in serotoninergic system function. Frequent anxiety recurrence, resistance, and drug adverse effects have driven searches for new therapies. We initially evaluated the anxiolytic-like activity of 3-selanyl-benzo[b]furan compounds (SeBZF1-5) (50 mg/kg, i.g.) in male Swiss mice using the light-dark test (LDT). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) exhibited anxiolytic-like activity. SeBZF3 anxiolytic-like effects were also observed in the novelty-suppressed feeding test (NSFT) (50 mg/kg) and elevated plus-maze test (EPMT) (25 and 50 mg/kg). In the EPMT, anxiolytic-like effects of SeBZF3 (50 mg/kg) were abolished by pretreatment with p-chlorophenylalanine, a selective tryptophan hydroxylase inhibitor (100 mg/kg, i.p. for 4 days), suggesting the involvement of serotonergic mechanisms. Furthermore, we conducted experiments to investigate the synergistic effects of SeBZF3 subeffective doses (5 mg/kg, i.g.) in combination with fluoxetine (a selective serotonin reuptake inhibitor, 5 mg/kg, i.p.) or buspirone (a partial agonist of the 5-HT1A receptor, 2 mg/kg, i.p.). This coadministration resulted in pronounced synergistic effects. We also examined the effects of repeated oral treatment with SeBZF3 at doses of 1 and 5 mg/kg over 14 days and both reduced anxiety signals. In vitro and ex vivo findings revealed that SeBZF3 inhibited cerebral MAO-A activity. These findings collectively imply the potential involvement of serotonergic mechanisms in the anxiolytic-like activity of SeBZF3 in mice. These data offer contributions to the research field of organoselenium compounds and anxiolytics, encouraging the broadening of the search for new effective drugs while offering improved side effect profiles.
RESUMO
Major depressive disorder (MDD) is a psychiatric disorder that affects a large portion of the population, with dysregulation of the serotonergic system, which is deeply involved in both the pathophysiology of MDD and mechanism of action of many antidepressants. Current pharmacological therapies do not meet the neurobiological needs of all depressed individuals, making the development of new antidepressants necessary. In recent decades, compounds containing triazoles have become promising due to their range of biological activities, including antidepressant activity. In this study, we evaluated the antidepressant-like effect of a hybrid containing triazole and acetophenone, 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one (ETAP) (0.5-5 mg/kg), in the forced swimming test (FST) and tail suspension test (TST) in mice, as well as the involvement of the serotonergic system in this effect. Our findings demonstrated that ETAP exhibited an antidepressant-like effect from the dose of 1 mg/kg and that this effect is modulated by 5-HT2A/2C and 5-HT4 receptors. We also demonstrated that this effect may be related to inhibition of monoamine oxidase A activity in the hippocampus. Additionally, we evaluated the in silico pharmacokinetic profile of ETAP, which predicted its penetration into the central nervous system. ETAP exhibited a low potential for toxicity at a high dose, making this molecule interesting for the development of a new therapeutic strategy for MDD.
Assuntos
Transtorno Depressivo Maior , Serotonina , Camundongos , Animais , Serotonina/fisiologia , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Natação/psicologia , Elevação dos Membros Posteriores/psicologia , Depressão/tratamento farmacológicoRESUMO
Depression is a multifactorial and heterogeneous disease with several neurobiological mechanisms underlying its pathophysiology, including dysfunctional glutamatergic neurotransmission, which makes the exploration of the glutamate pathway an interesting strategy for developing novel rapid-acting antidepressant treatments. In the present study, we aimed to evaluate the possible glutamatergic pathway relation in the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF1 administration at effective (50 mg/kg) or subeffective (1 mg/kg) doses by intragastric route (ig). TST and the open-field test (OFT) were employed in all behavioral experiments. The pretreatment of mice with N-methyl-D-aspartate (NMDA) (0.1 pmol/site, intracerebroventricular, icv, a selective agonist of the NMDA receptors), D-serine (30 µg/site, icv, a co-agonist at the NMDA receptor), arcaine (1 mg/kg, intraperitoneal, ip, an antagonist of the polyamine-binding site at the NMDA receptor), and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (2,5 µg/site, icv, an antagonist of the AMPA/kainate type of glutamate receptors) inhibited the antidepressant-like effects of SeBZF1 (50 mg/kg, ig) in the TST. Coadministration of a subeffective dose of SeBZF1 with low doses of MK-801 (0.001 mg/kg, ip, a non-competitive NMDA receptor antagonist) or ketamine (0.1 mg/kg, ip, a non-selective antagonist of the NMDA receptors) produced significant antidepressant-like effects (synergistic action). These findings suggest the involvement of the glutamatergic system, probably through modulation of ionotropic glutamate receptors, in the antidepressant-like action of SeBZF1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects.
Assuntos
Benzofuranos , Ketamina , Masculino , Camundongos , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Receptores de N-Metil-D-Aspartato , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ketamina/farmacologia , Benzofuranos/farmacologia , Elevação dos Membros PosterioresRESUMO
Synthetic glucocorticoid administration has been reported to play a role in depression and cognitive decline. The present study investigated the 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) effects against the depressive-like behavior, memory impairment, and neurochemical alterations caused by acute dexamethasone administration in female Swiss mice. A dexamethasone dose-response curve (0.07-0.5 mg/kg, subcutaneous route, s.c.) was initially performed to validate the depressive-like behavior induction, in which the 0.25 mg/kg dose was more effective. Two experimental sets were performed to test the SeBZF1 (5 and 50 mg/kg, intragastric route, i.g.) pharmacological effect in this animal model. The 1st set revealed that the SeBZF1 reverses the dexamethasone-induced depressive-like behavior in the tail suspension test and in the splash test. In the 2nd experimental set, the compound effects of reversing the depressive-like behavior in the forced swimming test and the memory deficit in the Y-maze test induced by acute treatment with dexamethasone were demonstrated. Furthermore, SeBZF1 reversed the increase in the monoamine oxidase (MAO) activity in the prefrontal cortex (isoforms A and B) and in the hypothalamus (isoform A) caused by dexamethasone. However, no changes were observed in hippocampal MAO activity. Furthermore, animals treated with dexamethasone and SeBZF1 demonstrated a partially lower acetylcholinesterase activity in the prefrontal cortex compared with the induced group. In summary, the present study demonstrated that SeBZF1 reverses depressive-like behavior and memory deficits caused by acute dexamethasone treatment in female Swiss mice. Possibly the compound exerts its antidepressant-like action by increasing the availability of monoamines, while its effects on memory are still partially understood.
Assuntos
Benzofuranos , Disfunção Cognitiva , Animais , Camundongos , Feminino , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Acetilcolinesterase , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Comportamento Animal , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Benzofuranos/efeitos adversos , Monoaminoxidase , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/complicaçõesRESUMO
The present study investigated the antidepressant-like potential of a functionalized 3-selanyl benzo[b]furan (SeBZF) in male Swiss mice. To evaluate possible antidepressant-like actions, the compounds SeBZF1-5 (50 mg/kg, intragastric, i.g., route) were acutely screened in the tail suspension tests (TSTs). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) was then selected. Dose-response and time-response curves revealed that SeBFZ3 exerts antidepressant-like effects in the TST (5-50 mg/kg) and forced swimming test (FST; 50 mg/kg). Additional tests demonstrated that pretreatment with receptor antagonists WAY100635 (5-HT1A; 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/C; 1 mg/kg, intraperitoneal, i.p.), or ondansetron (5-HT3; 1 mg/kg, i.p.) blocked the SeBZF3 antidepressant-like effects (50 mg/kg) in the TST. In addition, the coadministration of subeffective doses of SeBZF3 (1 mg/kg, i.g.) and fluoxetine (a selective serotonin reuptake inhibitor; 5 mg/kg, i.p.) produced synergistic action. A high dose of SeBZF3 (300 mg/kg) did not produce oral acute toxicity. The present results provide evidence for the antidepressant-like action of SeBZF3 and its relative safety, as well as predict the possible interactions with the serotonergic system, aiding in the development of novel options to alleviate psychiatric disabilities.
Assuntos
Antidepressivos , Serotonina , Masculino , Camundongos , Animais , Serotonina/fisiologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Fluoxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Natação/psicologia , Elevação dos Membros Posteriores/métodos , Elevação dos Membros Posteriores/psicologia , Depressão/tratamento farmacológicoRESUMO
RATIONALE: Depression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results. OBJECTIVES AND METHODS: To evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50 mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300 mg/kg). RESULTS: MeSeI administered 30 min before the FST and the TST reduced immobility time at doses from 1 mg/kg and at 50 mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50 mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, intraperitoneally-i.p. for 4 days), with ketanserin, a 5-HT2A/2C receptor antagonist (1 mg/kg, i.p.), and with GR113808, a 5-HT4 receptor antagonist (0.1 mg/kg, i.p.), but not with WAY100635, a selective 5-HT1A receptor antagonist (0.1 mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT3 receptor antagonist (1 mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT2A, 5 -HT2C, and 5-HT4 receptors by molecular docking. MeSeI (300 mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice. CONCLUSION: In summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression.
Assuntos
Depressão , Indolizinas , Masculino , Feminino , Animais , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Serotonina/metabolismo , Simulação de Acoplamento Molecular , Atividade Motora , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Natação , Indolizinas/farmacologia , Elevação dos Membros PosterioresRESUMO
Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders with high rates of prevalence and mortality. MDD is pathophysiologically complex, and treatment options are limited. Blueberries are rich in polyphenols and have neuroprotective potential. The aim of this study was to investigate the effects of blueberry extract on neuroinflammatory and neuroplasticity parameters, as well as Na+/K+-ATPase, monoamine oxidase-A (MAO-A), and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus of mice subject to lipopolysaccharide (LPS)-induced depressive-like behavior. We also analyzed the interaction between anthocyanins and indoleamine 2 3-dioxygenase (IDO). Male Swiss mice (60-day-old) received vehicle, fluoxetine (20 mg/kg), or blueberry extract (100 or 200 mg/kg) intragastrically for 7 days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, the mice were subjected to behavioral tests. Both fluoxetine and blueberry extract (200 mg/kg) decreased the immobility time in the forced swim test, without affecting locomotor activity. Fluoxetine attenuated the decrease of Na+/K+-ATPase in the cerebral cortex, while blueberry extract promoted this same effect in the hippocampus. Additionally, fluoxetine and blueberry extract attenuated the decrease in the activity of MAO-A in the hippocampus. Blueberry extract (200 mg/kg) also prevented LPS-induced increase in AChE activity in the hippocampus as well as LPS upregulation of relative mRNA expression of tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-10 in the cerebral cortex. Molecular docking analysis revealed binding sites for malvidin 3-galactoside (- 7.8 kcal/mol) and malvidin 3-glucoside (- 7.9 kcal/mol) residues with IDO. Taken together, these results indicate that blueberry extract improved depression-like behavior and attenuated the neurochemical and molecular changes in the brains of mice challenged with LPS.
Assuntos
Transtorno Depressivo Maior , Lipopolissacarídeos , Masculino , Animais , Camundongos , Lipopolissacarídeos/toxicidade , Antocianinas/metabolismo , Fluoxetina/farmacologia , Doenças Neuroinflamatórias , Transtorno Depressivo Maior/metabolismo , Acetilcolinesterase/metabolismo , Simulação de Acoplamento Molecular , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/metabolismo , Hipocampo/metabolismo , Encéfalo/metabolismo , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Monoaminoxidase/metabolismo , Comportamento AnimalRESUMO
The monoaminergic dysfunction plays a central role in major depressive disorder (MDD), a mental disturbance associated with constant feeling of sadness and lack of interest. The available treatments do not present a desirable efficacy and some of them provoke several adverse effects. In this context, organoselenium compounds and molecules containing the indolizine nucleus have demonstrated interesting pharmacological properties, including antidepressant-like effects. In this study, the antidepressant-like effect of 2-phenyl-1-(phenylselanyl)indolizine (SeI), a selenium-containing indolizine derivative, was investigated on the forced swimming test (FST) and on the tail suspension test (TST) in male Swiss mice. The involvement of the serotonergic system in this effect was also accessed. The selenium compound SeI (10-100 mg/kg, intragastrical (i.g.)) was administered 0.5 h before the behavioral tests, and it diminished the immobility on both FST and TST experiments, which is an indication of antidepressant-like effect. No changing in the locomotor motion was observed in the open-field test (OFT). The anti-immobility effect of SeI was not altered by the preadministration of the selective serotonergic receptor antagonists ondansetron (1 mg/kg, intraperitoneally (i.p.), antagonist of 5-HT3 receptor) and WAY100635 (0.1 mg/kg, subcutaneous route (s.c.), antagonist of 5-HT1A receptor). In contrast, the preadministration of ketanserin (1 mg/kg, i.p., antagonist of 5-HT2A/C receptor) blocked this effect, demonstrating that the antidepressant-like effect of SeI involves 5-HT2A/C. In addition, molecular docking studies showed a strong interaction between SeI and the receptors of 5-HT2A and 5-HT2C. The toxicological results demonstrated that SeI has low potential to cause adverse effects in mice. It was found that the antidepressant-like effect of SeI is related to modulation of the serotonergic system, and this selenium compound could be included in new treatment approaches for MDD.
Assuntos
Transtorno Depressivo Maior , Indolizinas , Compostos de Selênio , Animais , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Elevação dos Membros Posteriores , Masculino , Camundongos , Simulação de Acoplamento Molecular , Serotonina/fisiologia , NataçãoRESUMO
Pain strongly affects public health, both because of the patient suffering and the socioeconomic impact. The available drugs for pain treatment are not fully effective and have many adverse effects. Therefore, there is a need to obtain new analgesic compounds. This study evaluated the antinociceptive effect of N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), an organoselenium compound containing the benzamide moiety, through time (15-120 min) and dose-response (1-50 mg/kg) curves in thermal and chemical mice models of nociception, as well as the involvement of the serotonergic system in this effect. The open-field test (OFT) was carried out to assess locomotor activity. SePB (10 mg/kg) induced an increase in the latency to nociception response in the tail immersion test from 30 min. In the dose-response curves, SePB at different doses reduced latency time to nociceptive response in the tail immersion and hot plate tests, and reduced the licking time in the glutamate test, demonstrating antinociceptive effect, without altering the locomotor activity of mice. WAY100635 (0.5 mg/kg, subcutaneously, a 5-HT1A receptor antagonist), ketanserin (0.3 mg/kg, intraperitoneally, a 5-HT2A/2C receptor antagonist), but not ondansetron (0.5 mg/kg, intraperitoneally, a 5-HT3 receptor antagonist), administered 15 min before SePB, prevented the increased latency to nociceptive response induced by SePB in the tail immersion test, demonstrating that 5-HT1A and 5-HT2A/2C receptors are involved in the antinociceptive effect of SePB. Upon more studies evaluating SePB antinociceptive effects in chronic pain models and its toxicity, this compound could be indicated as an interesting molecule to treat pain.
Assuntos
Analgésicos , Serotonina , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Camundongos , Dor/tratamento farmacológicoRESUMO
Chronic pain and depression often coexist sharing common pathological mechanisms, and available analgesics and antidepressants have demonstrated limited clinical efficacy. Evidence has demonstrated that neuronal oxidative stress, apoptosis, and also glucocorticoid receptor dysregulation facilitate the occurrence and development of both chronic pain and depression. This study evaluated the effect of the organoselenium compound m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] in the pain-depression comorbidity induced by reserpine. Mice were treated with reserpine 0.5 mg/kg for 3 days (intraperitoneal, once a day), and in the next 2 days, they were treated with (m-CF3-PhSe)2 10 mg/kg (intragastric, once a day). Thirty minutes after the last administration of (m-CF3-PhSe)2, mice were subjected to the behavioral testing. (m-CF3-PhSe)2 treatment reverted the reserpine-increased thermal hyperalgesia and depressive-like behavior observed in the hot-plate test and forced swimming test, respectively. Reserpine provoked a decrease of crossings and rearings in the open-field test, while (m-CF3-PhSe)2 presented a tendency to normalize these parameters. Reserpine and/or (m-CF3-PhSe)2 treatments did not alter the locomotor activity of mice observed in the rota-rod test. These effects could be related to modulation of oxidative stress, apoptotic pathway, and glucocorticoid receptors, once (m-CF3-PhSe)2 normalized thiobarbituric acid reactive substances and 4-hydroxynonenal modified protein levels, markers of lipoperoxidation, poly(ADP-ribose) polymerase cleaved/total ratio, and glucocorticoid receptor levels increased by reserpine in the hippocampus. Considering that pain-depression dyad is a complex state of difficult treatment, this organoselenium compound could raise as an interesting alternative to treat pain-depression condition.
Assuntos
Dor Crônica/tratamento farmacológico , Depressão/tratamento farmacológico , Compostos de Organossilício/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Receptores de Glucocorticoides , Reserpina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Dor Crônica/induzido quimicamente , Dor Crônica/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Compostos de Organossilício/farmacologia , Estresse Oxidativo/fisiologia , Receptores de Glucocorticoides/metabolismo , Resultado do TratamentoRESUMO
AIMS: Obesity is associated with a spectrum of hepatic abnormalities that can be experimentally induced by injections of monosodium glutamate (MSG) in neonatal rodents. We investigated the protective actions of the repeated therapy with 4-phenylselenyl-7-chloroquinoline (4-PSQ), a quinoline derivative containing selenium, on damage to the liver triggered by early postnatal administration of MSG in male Wistar rats. MAIN METHODS: Neonatal rats received MSG (4 g/kg, subcutaneous route) or saline (1 ml/kg) from 5 to 14 postnatal day (PND) to induce obesity with consequent damages in the liver. 4-PSQ treatment (5 mg/kg) or canola oil (1 ml/kg) was administered from 60 to 76 PND by the intragastric route. On 76 PND, animals were anesthetized for blood and liver collection. Plasma markers of hepatic function, hepatic lipoperoxidation levels and histology analysis of liver tissue were assessed. KEY FINDINGS: Our data revealed that treatment with 4-PSQ reverted the increase in plasma transaminases activities observed in MSG rats. Treatment with 4-PSQ reduced plasma lactate levels in obese rats. In the liver, MSG elevated the content of lipoperoxidation which was reverted by 4-PSQ administrations. Lastly, 4-PSQ therapy attenuated the histological alterations induced by MSG. SIGNIFICANCE: Together, the results indicate a hepatoprotective action of repeated treatment with 4-PSQ in obese rats.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Aromatizantes/efeitos adversos , Fígado/efeitos dos fármacos , Compostos Organosselênicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Quinolinas/uso terapêutico , Glutamato de Sódio/efeitos adversos , Animais , Animais Recém-Nascidos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/patologia , Masculino , Ratos WistarRESUMO
Some brain diseases are associated with oxidative stress and altered monoamine oxidase (MAO) activity. The objective of this study was to evaluate the antioxidant and neuroprotective actions through MAO inhibition of 3-(pyridin-2-yl)-2-(pyridine-2-ylimino) thiazolidin-4-one (PPIT, a synthetic molecule containing a thiazolidinone nucleus), as well as its effects on toxicity parameters in Swiss female mice. Five in vitro assays were carried out to verify the PPIT antioxidant capacity: protein carbonylation (PC), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picryl-hydrazil (DPPH), ferric ion (Fe3+ ) reducing antioxidant power (FRAP), and superoxide dismutase (SOD)-like activity. The results showed that PPIT reduced the level of PC in the homogenate of the brain. This compound did not demonstrate SOD mimetic activity, but it acted as a free radical scavenger (ABTS and DPPH) and exhibited reducing activity in the FRAP assay. In addition, the effects of PPIT on cerebral MAO activity (MAO-A and B isoforms) were investigated in vitro. Our data revealed inhibition of the MAO-B activity by PPIT with no effects on MAO-A. Lastly, an acute oral toxicity test was conducted in mice. No changes in food intake, body weight, and biochemical markers of kidney and liver damage were detected in mice treated with a high dose of PPIT (300 mg/kg). In conclusion, the present study demonstrated that PPIT exhibits antioxidant activity and selectively inhibits the MAO-B isoform without causing apparent toxicity. These findings suggest PPIT as a potential therapeutic candidate to be tested in preclinical models of brain diseases involving perturbations of MAO-B activity and redox status.
Assuntos
Encéfalo/enzimologia , Sequestradores de Radicais Livres/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Animais , Encefalopatias/tratamento farmacológico , Encefalopatias/enzimologia , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Masculino , Camundongos , Inibidores da Monoaminoxidase/efeitos adversos , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/químicaRESUMO
RATIONALE: Major depressive disorder is a psychiatric disorder that requires considerable attention, since it dramatically impairs the quality of life of the sufferers. The available treatments do not have the efficacy needed, often presenting several side effects. Organoselenium compounds and benzamides have presented some pharmacological properties, among them an antidepressant-like effect. OBJECTIVES AND METHODS: This study evaluated the antidepressant-like effect of N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), an organoselenium compound containing a benzamide moiety, on the forced swimming test (FST) and the tail suspension test (TST) in mice, as well as the involvement of the serotonergic system in its effect. RESULTS: SePB, tested after different times (15-120 min) and doses (1-50 mg/kg, intragastrically (i.g.)), reduced immobility of male mice during FST and TST, without changing locomotor activity in the open-field test (OFT), demonstrating its antidepressant-like effect. SePB (10 mg/kg) also produced an antidepressant-like effect in female mice in the TST. The preadministration of the serotonin (5-HT) depletor p-chlorophenylalanine (pCPA; 100 mg/kg, intraperitoneal route (i.p.) once daily for 4 days) prevented the anti-immobility effect of SePB, indicating that the serotonergic system is involved in the SePB antidepressant-like effect. The preadministration of the selective serotonergic receptor antagonists WAY100635 (0.1 mg/kg, subcutaneous route (s.c.), a selective 5-HT1A receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT2A/2C receptor antagonist), and ondansetron (1 mg/kg, i.p., a selective 5-HT3 receptor antagonist) also prevented the anti-immobility effect of SePB, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. CONCLUSION: The search for new antidepressants drugs is a noteworthy goal. This study has described a new compound with an antidepressant-like effect, whose mechanism of action is related to modulation of the serotonergic system.