RESUMO
In the pursuit of new lead compounds with fewer side effects than opioids, the novel synthetic phytochemical core, 3,3-dibromoflavanone (3,3-DBF), has emerged as a promising candidate for pain management. Acute assays demonstrated dose-dependent central and peripheral antinociceptive activity of 3,3-DBF through the µ-opioid receptor. This study aimed to explore repeated administration effects of 3,3-DBF in mice and compare them with morphine. Mice were treated with 3,3-DBF (30 mg/kg), morphine (6 mg/kg), or vehicle for 10 days, alongside single-treatment groups. Unlike morphine, 3,3-DBF demonstrated antinociceptive effects in the hot plate test without inducing tolerance. Locomotor activity and motor coordination tests (evaluated through the inverted screen and rotarod tests) revealed no significant differences between the 3,3-DBF-treated and control groups. The gastrointestinal transit assay indicated that 3,3-DBF did not induce constipation, in contrast to morphine. Furthermore, withdrawal signs assessed with the Gellert-Holtzman scale were not comparable to morphine. Additionally, 3,3-DBF exhibited antidepressant-like activity, reducing immobility time in the forced swimming and tail suspension tests, akin to imipramine. In summary, 3,3-DBF demonstrated antinociceptive effects without inducing tolerance or dependence and exhibited antidepressant properties. These findings highlight the potential of 3,3-DBF as a promising therapeutic agent for pain management and its comorbidities, offering advantages over morphine by minimizing side effects.
Assuntos
Analgésicos , Antidepressivos , Flavonoides , Morfina , Animais , Morfina/farmacologia , Morfina/uso terapêutico , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/química , Masculino , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/química , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonoides/química , Dor/tratamento farmacológico , Manejo da Dor/métodos , Atividade Motora/efeitos dos fármacosRESUMO
OBJECTIVE: This study mainly explores (2R,6R; 2S,6S)-HNK and its compounds whether there are antidepressant effects. METHODS: Four HNK compounds were obtained from 2-(Chlorophenyl) Cyclopentylmethanone. Forced swimming test, locomotor sensitization test, and conditioned location preference test were used to screen the antidepressant activity of the synthesized target compounds. RESULTS: In the case of 10 mg HNK treatment, compared with saline, the immobile time of mice in the HNK group, I5 group and I6 group at 1 h and 7 days had statistical significance. In the case of 10 mg HNK treatment, compared with saline, the immobile time of compound C and D groups in the glass cylinder area was significantly different. In the locomotor sensitization test, the movement distance of compound C and D groups on day 15 and day 7 mice increased significantly compared with the first day. In the conditioned place preference experiment, compound C and compound D induced conditioned place preference in mice compared with the Veh group. CONCLUSION: The results of the forced swimming test, locomotor sensitization test, and conditioned location preference test showed that compounds C and D may have certain anti-depressant activity. However, HNK exerts a rapid and significant antidepressant effect within 1 week, but the duration is short.
Assuntos
Antidepressivos , Ketamina , Atividade Motora , Natação , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos , Masculino , Ketamina/farmacologia , Ketamina/análogos & derivados , Atividade Motora/efeitos dos fármacos , Fatores de Tempo , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Reprodutibilidade dos TestesRESUMO
SUMMARY: Spinal cord injury (SCI) usually arises from compression due to traffic accidents and falls, resulting in varying degrees of movement, sensory loss, and possible paralysis. Glabridin (Gla) is a natural compound derived from licorice. It significantly affects drug development and medicine because of its anti-inflammatory, anti-oxidative, anti-tumoral, antibacterial, bone protective, cardiovascular protective, neuroprotective, liver protective, anti-obesity, and anti-diabetic properties. Various methods were employed to administer Gla to SCI mice in order to investigate its impact on the recovery of motor function. The mice were allocated into four cohorts using a randomization procedure. In the sham cohort, solely the lamina of vertebral arch was surgically exposed without causing any harm to the spinal cord tissue. Conversely, the injury cohort was subjected to spinal cord tissue damage and received no treatment thereafter. The mice in the remaining two cohorts received a dosage of 40 mg/kg Gla every two days via either intraperitoneal or intrathecal injection for a duration of 42 d following spinal cord injury. We conducted behavioral tests utilizing the Basso Mouse Scale score and gait analysis techniques. Magnetic resonance imaging and hematoxylin and eosin were employed to evaluate scar tissue formation. Systemic inflammation in mice was evaluated by employing an enzyme-linked immunosorbent assay. Gla promoted motor function recovery in mice following SCI and improved the pathological environment in the damaged area. These alterations were more evident in mice subjected to the intrathecal injection method. Intraperitoneal injections appear to be more beneficial for controlling systemic inflammatory responses. Although more intensive studies are required, Gla exhibits promising clinical potential as a cost-effective dietary phytochemical.
La lesión de la médula espinal (LME) generalmente surge de la compresión producto de caídas y accidentes de tránsito, lo que resulta en alteraciones del movimiento, pérdida sensorial y posible parálisis. La Glabridina (Gla) es un compuesto natural derivado del regaliz, constituyéndose en un aporte significativo para el desarrollo de fármacos y la medicina debido a sus propiedades antiinflamatorias, antioxidantes, antitumorales, antibacterianas, osteoprotectoras, cardioprotectoras, neuroprotectoras, hepatoprotectoras, antidiabéticas y contra la obesidad. En el presente trabajo se emplearon varios métodos para administrar Gla a ratones con lesión medular con el fin de investigar su impacto en la recuperación de la función motora. Los ratones fueron distribuidos en cuatro grupos mediante un procedimiento de aleatorización. En el grupo simulado, únicamente se expuso quirúrgicamente la lámina del arco vertebral sin causar ningún daño al tejido de la médula espinal. Por el contrario, el grupo lesionado fue sometido a daño del tejido de la médula espinal, sin recibir tratamiento posterior. Los ratones de los dos grupos restantes recibieron una dosis de 40 mg/kg de Gla cada dos días mediante inyección intraperitoneal o intratecal durante 42 días después de la lesión de la médula espinal. Fueron realizadas pruebas de comportamiento utilizando la puntuación de la escala Basso Mouse y técnicas de análisis de la marcha. Se emplearon imágenes por resonancia magnética y se aplicaron tinciones histológicas (Hematoxilina & Eosina) en muestras para evaluar la formación de tejido cicatricial. La inflamación sistémica en ratones se evaluó mediante el empleo de un ensayo inmunoabsorbente ligado a enzimas. Gla promovió la recuperación de la función motora en ratones después de una lesión medular y mejoró el entorno patológico en el área dañada. Estas alteraciones fueron más evidentes en ratones sometidos al método de inyección intratecal. Las inyecciones intraperitoneales parecen ser más beneficiosas para controlar las respuestas inflamatorias sistémicas. Aunque se requieren estudios más intensivos, Gla exhibe un potencial clínico prometedor como fitoquímico dietético rentable.
Assuntos
Animais , Feminino , Camundongos , Fenóis/administração & dosagem , Traumatismos da Medula Espinal/tratamento farmacológico , Isoflavonas/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Sobrevivência Celular , Imunofluorescência , Fármacos Neuroprotetores , Recuperação de Função Fisiológica , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacosRESUMO
Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.
Assuntos
Ketamina , Monoaminoxidase , Estresse Oxidativo , Resveratrol , Animais , Resveratrol/farmacologia , Resveratrol/administração & dosagem , Ketamina/farmacologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Monoaminoxidase/metabolismo , Monoaminoxidase/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Interleucina-6/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Interação Social/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Atividade Motora/efeitos dos fármacosRESUMO
Crack cocaine is a highly addictive and potent stimulant drug. Animal studies have shown that the cholinergic system plays a role in neurotoxicity induced by cocaine or its active metabolites inhalation. Behavioral alterations associated with crack cocaine use include hyperactivity, depressed mood, and decreased seizure threshold. Here we evaluate the acetylcholinesterase (AChE) and reactive oxygen species (ROS) activity, behavioral profile, and the threshold for epileptic seizures in rats that received intrahippocampal pilocarpine (H-PILO) followed by exposure to crack cocaine (H-PILO + CRACK). Animals exposed to H-PILO + CRACK demonstrated increased severity and frequency of limbic seizures. The AChE activity was reduced in the groups exposed to crack cocaine alone (CRACK) and H-PILO + CRACK, whereas levels of ROS remained unchanged. In addition, crack cocaine exposure increased vertical locomotor activity, without changing water and sucrose intake. Short-term memory consolidation remained unchanged after H-PILO, H-PILO + CRACK, and CRACK administration. Overall, our data suggest that crack cocaine inhalation reduced the threshold for epileptic seizures in rats submitted to low doses of pilocarpine through the inhibition of AChE. Taken together, our findings can be useful in the development of effective strategies for preventing and treating the harmful effects of cocaine and crack cocaine on the central nervous system.
Assuntos
Acetilcolinesterase , Cocaína Crack , Pilocarpina , Ratos Wistar , Convulsões , Animais , Masculino , Acetilcolinesterase/metabolismo , Ratos , Pilocarpina/toxicidade , Convulsões/induzido quimicamente , Administração por Inalação , Modelos Animais de Doenças , Espécies Reativas de Oxigênio/metabolismo , Atividade Motora/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
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
Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT1-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1-R blockade altered the performance of social interaction. Our results highlight the AT1-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.
Assuntos
Anfetamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Angiotensina II , Benzimidazóis , Compostos de Bifenilo , Corpo Estriado , Dopamina , Animais , Anfetamina/farmacologia , Masculino , Dopamina/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Benzimidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ratos Wistar , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Interação Social/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Parkinson's disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6 h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.
Assuntos
Modelos Animais de Doenças , Transtornos Parkinsonianos , Reserpina , Privação do Sono , Animais , Masculino , Reserpina/farmacologia , Privação do Sono/complicações , Camundongos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Catalepsia/induzido quimicamente , Estresse Oxidativo/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Atividade Motora/fisiologia , Atividade Motora/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Anedonia/fisiologia , Anedonia/efeitos dos fármacosRESUMO
Believed to cause damage to the nervous system and possibly being associated with neurodegenerative diseases, deltamethrin (DM) is a type II pyrethroid used in pest control, public health, home environment, and vector control. The objective of this study was to evaluate the motor, cognitive and emotional changes associated with dopaminergic and BDNF imbalance after DM exposure in rats. Sixty Wistar rats (9-10 months-old) were used, under Ethics Committee on Animal Research license (ID 19/2017). The animals were randomly divided into four groups: control (CTL, 0.9% saline), DM2 (2 mg DM in 1.6 mL 0.9% saline), DM4 (4 mg of DM in 1.6 mL of 0.9% saline), and DM8 (8 mg of DM in 1.6 mL of 0.9% saline). DM groups were submitted to 9 or 15 inhalations, one every 48 h. Half of the animals from each group were randomly selected and perfused 24 h after the 9th or 15th inhalation. Throughout the experiment, the animal's behavior were evaluated using catalepsy test, open field, hole-board test, Modified Elevated Plus Maze, and social interaction. At the end of the experiments, the rats were perfused transcardially and their brains were processed for Tyrosine Hydroxylase (TH) and Brain derived neurotrophic factor (BDNF) immunohistochemistries. The animals submitted to 9 inhalations of DM showed a reduction in immunoreactivity for TH in the Substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and dorsal striatum (DS) areas, and an increase in BDNF in the DS and CA1, CA3 and dentate gyrus (DG) hippocampal areas. Conversely, the animals submitted to 15 inhalations of DM showed immunoreactivity reduced for TH in the SNpc and VTA, and an increase in BDNF in the hippocampal areas (CA3 and DG). Our results indicate that the DM inhalation at different periods induce motor and cognitive impairments in rats. Such alterations were accompanied by dopaminergic system damage and a possible dysfunction on synaptic plasticity.
Assuntos
Ansiedade/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Inseticidas/farmacologia , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Nitrilas/farmacologia , Piretrinas/farmacologia , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Exposição por Inalação , Inseticidas/administração & dosagem , Nitrilas/administração & dosagem , Piretrinas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Comportamento SocialRESUMO
Methylmercury (MeHg) and ethylmercury (EtHg) are important mercury organic forms in terms of human poisoning. Since the comparative effects of compounds are mainly in vitro, this study was designed to investigate the toxicities induced by MeHg and EtHg in an in vivo study using adult Drosophila melanogaster (D. melanogaster). Firstly, we performed a survival curve, where the flies were fed on a medium containing MeHg and EtHg at concentrations ranging from 2.5 to 200 µM, until the end of their lifespan. After that, the concentrations 25 and 200 µM of MeHg and EtHg were chosen to be tested in a short exposure for 5 days. The analysis of survival by Kaplan-Meier plot revealed that all concentrations of MeHg and EtHg reduced significantly the lifespan of the flies. Short exposure to both concentrations of MeHg and EtHg impaired the ability of flies in the climbing assay and induced lipid peroxidation. Only the flies exposed to the highest concentration had viability loss, thiol depletion, and increased reactive species (RS) and Hg levels in the whole body. Our findings indicate that MeHg and EtHg exhibit similar toxic effects in vivo, and that oxidative stress is a phenomenon behind the toxicity of both mercurials. The data obtained also reinforce the use of D. melanogaster as a useful organism for basic toxicological research.