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
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
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
Our previous study demonstrated that 2-phenylethynyl-butyltellurium (PEBT), an organotellurium compound, enhances memory in mice. In this study, the effects of PEBT on cognitive impairment induced by Aß25-35 were assessed by Morris water maze and step-down inhibitory avoidance tasks. Mice received a single intracerebroventricular injection of Aß25-35 (3 nmol/3 µl/per site) and a daily oral administration of PEBT (1 mg/kg, for 10 days). PEBT significantly improved Aß-induced learning deficits on the training session in the Morris water maze. At the probe trial session, PEBT significantly decreased the escape latency and increased the number of crossings in the platform local compared with the Aß-treated group. PEBT significantly improved Aß-induced memory impairment in the step-down inhibitory avoidance task. General locomotor activity was similar in all groups. This study showed that PEBT ameliorated the impairments of spatial and nonspatial long-term memory evaluated on Morris water maze and step-down inhibitory avoidance tasks, respectively. The results suggest that PEBT could be considered a candidate for the prevention of memory deficits such as those observed in Alzheimer's disease.