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1.
Chem Biol Interact ; 317: 108959, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001261

RESUMO

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect.


Assuntos
Amnésia/prevenção & controle , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Quinolinas/farmacologia , Amnésia/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , Camundongos , Atividade Motora/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Córtex Pré-Frontal/efeitos dos fármacos , Escopolamina/toxicidade , Transdução de Sinais
2.
Chem Biol Interact ; 317: 108941, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926916

RESUMO

m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] is an organoselenium molecule that displays multiple pharmacological actions, including the antinociceptive effect. The current study investigated the (m-CF3-PhSe)2 restorative properties in models of acute and chronic inflammatory pain induced by complete Freund's adjuvant (CFA). Male adult Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h (acute) or 14 days (subchronic) later they were treated with a single or repeated (m-CF3-PhSe)2 schedule via intragastric route, respectively. The mechanical and thermal hypernociceptive behaviors were assessed by von Frey hair and hot plate tests. Samples of injected paw were collected to evaluate the tissue edema and myeloperoxidase (MPO) activity while cerebral contralateral cortex samples were used to determine the inflammatory proteins content (subchronic protocol). The acute (m-CF3-PhSe)2 administration (1 and 10 mg/kg) reduced the hypernociceptive behavior and both paw thickness and MPO activity induced by CFA injection. In the subchronic protocol, the repeated administration with a low effective dosage of (m-CF3-PhSe)2 reduced the mechanical and thermal hypernociception as well as restored the edema and MPO activity in paw samples. In addition, the repeated treatment schedule mitigated the increase in TNF-α, IL-1ß and COX-2 content in cerebral contralateral cortex induced by CFA injection. Collectively, these data showed that (m-CF3-PhSe)2 presents anti-inflammatory properties, which could be mediated by an interplay between peripheral and central mechanisms of action, reinforcing the potential biological properties of the compound.


Assuntos
Inflamação/induzido quimicamente , Compostos de Organossilício/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacologia , Adjuvante de Freund/toxicidade , Inflamação/tratamento farmacológico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Compostos de Organossilício/administração & dosagem , Medição da Dor , Sintase do Porfobilinogênio/metabolismo , Carbonilação Proteica , Compostos de Sulfidrila/metabolismo
3.
J Stroke Cerebrovasc Dis ; 29(1): 104468, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31694784

RESUMO

OBJECTIVES: Intracerebral hemorrhage (ICH) is one of the leading causes of disability and mortality in adult, which lacks effective therapies. Edaravone has showed its neuroprotective effects after ischemia stroke, but its effects and possible mechanisms after ICH are poorly understood. Here, we investigated whether edaravone confers neuroprotection after ICH in rats and explored the potential mechanisms involved. METHODS: ICH was induced in the right basal ganglia of Sprague-Dawley rats by stereotacticly injection of 200 µl autologous blood. Edaravone (3 mg/kg) or vehicle (saline) was administered intravenously and NLRP3 selective antagonist (MCC950, 10 mg/kg) was intraperitoneally injected to study the potential mechanism. Water Morris Maze Test and Rotarod test were used to elucidate neurological function and Fluoro-Jade C was used to study neurodegeneration after ICH. Western blot assay, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to check the expression of molecules involved. RESULTS: As a result, we found that edaravone significantly alleviated brain edema and conferred the neurological deficits of rats after ICH. Hematoma increased NLRP3 expression in microglia, which was decreased by edaravone. Moreover, we demonstrated that edaravone shared a similar effect with MCC950 on alleviating neurodegeneration and decreasing the expression of IL-1ß, Caspase 1 and NF-κB in protein or mRNA. Lastly, edaravone and MCC950 both increased the number of Tuj-1 positive neuronal cells peripheral hematoma. CONCLUSIONS: The present study demonstrated that edaravone conducted neuroprotection after ICH partially via suppressing NF-κB-dependent NLRP3 in microglia, which contributed a novel evidence for clinic usage of edaravone after ICH.


Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Edaravone/farmacologia , Inflamassomos/metabolismo , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Caspase 1/metabolismo , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Interleucina-1beta/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais
4.
J Stroke Cerebrovasc Dis ; 29(1): 104483, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31727597

RESUMO

OBJECTIVE: Gastrodin, a glucoside of gastrodigenin, inhibits cerebral oxidant stress and apoptosis in multiple central nervous system injury, but its effect in intracerebral hemorrhage (ICH) remains unclear. This study investigated the effect of gastrodin on neuronal apoptosis and neurological deficits in rat ICH model. METHODS: In vitro experiments were performed using hematoma lysate-induced cell damage model in primary cortical neurons. Rat ICH model was produced by a caudatum injection of collagenase. Gastrodin was intraperitoneal injected after 2 hours following ICH. Cell viability, brain water content, neurological score, western blot, and immunofluorescence experiments were performed. RESULTS: Gastrodin significantly decreased hematoma lysate-induced reduction of cell viability and cell apoptosis in primary cortical neurons. Gastrodin significantly improved brain edema and neurological deficits post-ICH. Moreover, gastrodin administration significantly reduced levels of ROS, 8-OHDG, 3-Nitrotyrosine and MDA, while increased GSH-Px and SOD activity, and stimulated the upregulation of Keap1, Nrf2, and HO-1 signaling at 72 hours post-ICH. Furthermore, gastrodin significantly increased Bcl-2 expression, while reduced level of Bax, active caspase-3 and active caspase-9, also reduced the number of active caspase-3 or TUNEL positive neurons at 72 hours post-ICH. CONCLUSION: These results suggest that gastrodin is neuroprotective after ICH and the mechanism may be associated with the inhibition of oxidative stress and neuronal apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Álcoois Benzílicos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Glucosídeos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais
5.
Integr Zool ; 15(1): 40-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31149773

RESUMO

It is well known that environmental temperature influences several biological functions of ectotherms, notably in amphibians. The high permeability of anuran skin, associated with the effect of elevated environmental temperature, potentiates the dehydration process and this combination may restrict locomotor performance. Thoropa taophora is an endemic species from the Atlantic Rainforest whose tadpoles are semiterrestrial and predominantly diurnal, and are found in rocky seashores where they are exposed to sea spray and high temperatures. In this study we investigated how temperature and salinity conditions affect the locomotor performance in Thoropa taophora tadpoles. We also assessed how different osmotic concentrations affect the activity of the metabolic pathways that support muscle function. We measured the sprint speed of tadpoles of various sizes at different temperatures and salinities in the field. We also measured the activity of the enzymes pyruvate kinase (PK), lactate dehydrogenase (LDH) and citrate synthase (CS) in different temperatures and osmotic concentrations, and calculated the thermal sensitivity and the activity constants for each osmolality. Our results showed that, in general, sprint speed decreased with increasing temperature and salinity. However, whereas the effect of increased salinity was similar in smaller and larger tadpoles, increased temperature had a higher negative impact on sprint speed of larger tadpoles, thus indicating low thermal sensitivity of small tadpoles. PK and LDH thermal sensitivities and LDH constant of activity decreased as the osmolality increased. In conclusion, the locomotor capacity of tadpoles was decreased by temperature and salinity, which may be related to a decrease in anaerobic metabolism both in terms of sensitivity and total energy turnover through enzymatic activity. We discuss the ecological consequences, including the potential impacts on predator escape behavior promoted by changes in metabolism and locomotor performance in an early stage of development of this species.


Assuntos
Anuros/fisiologia , Temperatura Alta , Atividade Motora/efeitos dos fármacos , Salinidade , Cloreto de Sódio/farmacologia , Animais , Anuros/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Larva/efeitos dos fármacos , Larva/fisiologia , Atividade Motora/fisiologia , Cloreto de Sódio/administração & dosagem , Estresse Fisiológico
6.
Ecotoxicol Environ Saf ; 188: 109900, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31710868

RESUMO

Copper is an essential element in many biological processes, but may exert toxic effects at levels surplus to metabolic requirements. Herein we assess the effect of copper on zebrafish behaviour using two assays, namely the novel tank diving test and a T-maze test with food reward. Novel tank diving tests were conducted on days 0, 4, and 10 of a 10 day Cu exposure (at concentrations of 0.77 µM (25% of the 240 h LC50) and 1.52 µM (50% of the 240 h LC50) to assess the alterations of behavioural responses in repeating novel tank diving assays and the effect of Cu on these patterns. Results demonstrate habituation to novelty, which is an indicator of spatial memory. Copper exposure had no effect on the latency of entry into the upper zones of the tank, nor on the total time spent therein, but did cause a greater number of freezing bouts in comparison to the control group. Additionally, Cu exposure had no effect on the habituation responses of zebrafish. Using the T-maze assay, we tested the effect of prior exposure to Cu for 10 days on subsequent behavioural trainings. The T-maze protocol was based on associative learning, where a visual stimulus (colour) was linked with a natural stimulus (food). Results of the control group showed that zebrafish are able to perform associative learning tasks. Moreover, Cu was found to negatively affect the associative learning capabilities. Specifically, while zebrafish in the control group achieved a significant number of correct choices (leading to food reward) throughout the T-maze training, such a trend was not observed for Cu exposed fish. Thus at the exposure concentrations and exposure times considered herein, Cu has no determinative impact on instinctual behavioural responses of zebrafish in repeated novel tank diving assays but does limit the associative learning capabilities.


Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Cobre/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Carga Corporal (Radioterapia) , Cobre/metabolismo , Atividade Motora/efeitos dos fármacos , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/metabolismo
7.
Eur J Med Chem ; 185: 111824, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708184

RESUMO

In searching for more effective and safer antiepileptic drugs, a series of 2,5-disubstituted [1,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one derivatives were designed and synthesized. Spontaneous Ca2+ oscillations (SCOs) of cortical neurons were used for in vitro phenotypic screening. Maximal electroshock test (MES) and pentylenetetrazole (PTZ) test were used to access their anticonvulsant activity, and rotarod test was used to estimate their neurotoxicity. The active compounds in in vitro model are specifically effective in pentylenetetrazole (PTZ)-induced epilepsy model but not maximal electroshock (MES) model, more importantly with lower neurotoxicity as compared to commonly used drugs. Among them, compound 5c and 5e showed significant anticonvulsant activities in PTZ-induced epilepsy model with ED50 values at 31.81 mg/kg and 40.95 mg/kg, respectively. These compounds have improved neurotoxicity with protective index (PI = TD50/ED50) values at 17.22 and 9.09, respectively. Finally we demonstrated that compound 5c and 5e mainly acted on GABAA receptor as positive modulators but not sodium channels. Thus the present study has provided potential candidates for further investigation in epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Atividade Motora/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Triazóis/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/toxicidade , Células Cultivadas , Relação Dose-Resposta a Droga , Descoberta de Drogas , Eletrochoque , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pentilenotetrazol , Substâncias Protetoras/química , Substâncias Protetoras/toxicidade , Pirimidinas/química , Pirimidinas/toxicidade , Convulsões/induzido quimicamente , Relação Estrutura-Atividade , Triazóis/química , Triazóis/toxicidade
8.
Medicine (Baltimore) ; 98(50): e18331, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852127

RESUMO

This study assessed sex differences in cardiac and motor functions, quality of life (QoL), and mental status in Chinese chronic heart failure (CHF) patients after metoprolol treatment.This single-center prospective study, conducted from February 2013 to April 2016, included CHF patients (men and women) with resting heart rate (HR) >80 beats/min using metoprolol continuous release tablets. Metoprolol-induced changes in cardiac and motor functions, QoL, and mental status at 1, 3, 6, 9, and 12 months from baseline, within and between the sexes, were analyzed. Descriptive data were represented as counts, percentages, and mean ± standard deviation. Differences at various follow-up periods were compared using repeated measures one-way analysis of variance, followed by post hoc Dunnett's multiple comparison test. Statistical significance was considered at P < .05.Compared with men, women reported significantly higher systolic blood pressure (SBP) (122.28 ±â€Š6.76 vs 125.47 ±â€Š6.67 mm Hg, P < .05) and Veterans Specific Activity Questionnaire score (8.16 ±â€Š0.98 vs 8.47 ±â€Š0.89, P = .05) at 12 months. Men reported higher Hospital Anxiety and Depression Scale scores for depression than women at 1 month (10.27 vs 8.83, P < .05) and for anxiety at 12 months (8.4 vs 7.72, P < .05). Metoprolol significantly decreased HR and Minnesota Living with Heart Failure Questionnaire score in men (64.5 ±â€Š3.13 and 53.7 ±â€Š8.00) and women (65.38 ±â€Š3.32 and 53.85 ±â€Š8.42, respectively). Ejection fraction (%, men: 50.00 ±â€Š4.45, women: 50.72 ±â€Š4.09), cardiac index (L/min/m, men: 2.70 ±â€Š0.25, women: 2.78 ±â€Š0.23), 6-minute walk test distance (m, men: 414.41 ±â€Š20.84, women: 420.34 ±â€Š20.35), and short form-8 questionnaire scores (men: 52.05 ±â€Š1.94, women: 52.19 ±â€Š2.58) increased significantly in both the sexes (P < .001 for all) at 12 months. Copenhagen Burnout Inventory score significantly increased in men (mean score 62.43, P < .05).Metoprolol treatment improves cardiac and motor functions, QoL, and anxiety scores but causes greater depression and burnout in men and women. Sex was seen to affect mental status of CHF patients the most.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/psicologia , Metoprolol/uso terapêutico , Qualidade de Vida , Fatores Sexuais , Adulto , Idoso , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Grupo com Ancestrais do Continente Asiático/psicologia , China , Doença Crônica , Depressão/tratamento farmacológico , Depressão/etiologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento
9.
Life Sci ; 239: 117033, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697950

RESUMO

AIMS: Benzodiazepines (BZDs) produce various pharmacological actions by binding to and allosterically regulating GABAA receptors. Several in vitro studies have demonstrated diazepam, the prototypic BZD, produces a high-dose action that cannot be countered with the classical BZD-binding site antagonist flumazenil. Here, we investigate the existence and behavioral relevance of non-classical BZD binding sites in zebrafish larvae. MAIN METHODS: Zebrafish larvae were treated with a series of BZDs alone or combined with flumazenil, bicuculline (a non-selective GABAA receptor antagonist), or RO 15-4513 (a general BZD antagonist and a proposed antagonist interacting with α+/ß- interfaces in α4/6/ß3δ receptors), and their locomotor activities and behavioral phenotypes were recorded. KEY FINDINGS: Diazepam-induced hypolocomotion (sedation-like state) at low doses (10 and 20 mg L-1) was effectively antagonized by flumazenil or bicuculline, while diazepam-induced immobility (anesthesia-like state) at higher dose (30 mg L-1) was prevented by bicuculline (3 mg L-1) but not flumazenil, even at doses up to 150 mg L-1. Ro 15-4513 also failed to efficiently antagonize diazepam-induced immobility. Immobility induced by high dose of another 1,4-BZD, clonazepam, was also resistant to flumazenil. SIGNIFICANCE: These results provide direct in vivo evidence for non-classical BZD-binding sites, which may be located at the second transmembrane domain of GABAA receptors and contribute to BZD-induced anesthesia.


Assuntos
Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Azidas/farmacologia , Benzodiazepinas/toxicidade , Bicuculina/farmacologia , Sítios de Ligação/efeitos dos fármacos , Clonazepam/farmacologia , Relação Dose-Resposta a Droga , Feminino , Flumazenil/toxicidade , Antagonistas GABAérgicos/farmacologia , Moduladores GABAérgicos/toxicidade , Larva , Masculino , Peixe-Zebra
10.
Nat Neurosci ; 22(12): 1975-1985, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31611707

RESUMO

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ9-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Dronabinol/efeitos adversos , Dronabinol/farmacologia , Pregnenolona/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Dronabinol/antagonistas & inibidores , Endofenótipos , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Atividade Motora/efeitos dos fármacos , Inibição Neural/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Gravidez , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Ratos , Assunção de Riscos , Filtro Sensorial/efeitos dos fármacos , Filtro Sensorial/fisiologia , Caracteres Sexuais , Área Tegmentar Ventral/metabolismo
11.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547612

RESUMO

The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.


Assuntos
Bignoniaceae/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Flavonoides/farmacologia , Hiperalgesia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Modelos Animais de Doenças , Flavonoides/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/diagnóstico por imagem , Ácido Iodoacético/toxicidade , Atividade Motora/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Osteoartrite/induzido quimicamente , Osteoartrite/diagnóstico por imagem , Extratos Vegetais/química , Ratos , Ratos Wistar
12.
Molecules ; 24(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480324

RESUMO

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiologia , Catha/química , Extratos Vegetais/farmacologia , Receptor CB2 de Canabinoide/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Encéfalo/efeitos dos fármacos , Canabinoides/administração & dosagem , Canabinoides/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor CB2 de Canabinoide/agonistas , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Food Chem Toxicol ; 133: 110802, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493462

RESUMO

The aim of this study was to characterize the central effects of the Hyptis martiusii leaf essential oil (OEHM) and 1,8-cineole (eucalyptol) using behavioral animal models. Gas chromatography coupled to mass spectrometry (GC/MS) was used to characterize the chemical compounds present in the OEHM. For the behavioral tests, female Swiss mice treated with the OEHM (25, 50, 100 and 200 mg/kg, i.p.) and 1,8-cineole (50 mg/kg, i.p.) were used and subjected to the following tests: open field, elevated cross maze, rotarod, sodium pentobarbital- or ethyl ether-induced sleep time, pentylenetetrazol-induced convulsions, haloperidol-induced catalepsy, and ketamine-induced hyperkinesia. GC/MS analysis identified 20 constituents with the majority of them being monoterpenes and sesquiterpenes, with eucalyptol (1,8-cineol), the major sample compound (25.93%), standing out. The results showed the OEHM (25, 50 100 and 200 mg/kg, i.p.) and its major compound (50 mg/kg, i.p.) reduced animal motility in the open field test, increased pentobarbital- and ethyl ether-induced sleep time, as well as death latency in the pentylenetetrazole-induced convulsion model. However, the tested compounds were devoid of anxiolytic-like and myorelaxant activity. In addition, the OEHM (100 and 200 mg/kg, i.p.) and 1,8-cineole (50 mg/kg, i.p.) potentiated haloperidol-induced catalepsy and reduced ketamine-induced hyperkinesia. Taken together, the results suggest the OEHM has important hypnotic-sedative and antipsychotic-like effects, which appear to be due to the monoterpene 1,8-cineole, the major compound identified in the essential oil.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Eucaliptol/farmacologia , Hyptis/química , Óleos Voláteis/farmacologia , Animais , Eucaliptol/toxicidade , Feminino , Hipercinese/tratamento farmacológico , Ketamina , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Óleos Voláteis/toxicidade , Folhas de Planta/química , Sono/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-31494630

RESUMO

Background Short-term memory impairment is a neurodegenerative disease associated with oxidative stress. Bryophyllum pinnatum (Lam.) Oken of the family Crassulaceae is traditionally used in the treatment of diseases, such as cough, wounds, and kidney diseases. This study evaluates the effect of the aqueous extract of B. pinnatum (AEBP) leaves on acetylcholinesterase activity in carbon tetrachloride (CCl4)-induced short-term memory impairment in rats. Methods Thirty male Wistar albino rats were used in this study and were divided into six groups (n=5). Group I served as control, group II rats were induced with CCl4, while groups III-V animals were pretreated with silymarin (25 mg/kg body weight), 25 and 50 mg/kg body weight AEBP leaves, respectively, once daily by oral gavage for 14 days prior to a single intraperitoneal injection of CCl4. Animals in group VI received 50 mg/kg body weight AEBP only by oral gavage. Results Administration of carbon tetrachloride significantly increased (p<0.05) spontaneous alternation and locomotor function in rats when compared with the control group. Also, the levels of acetylcholinesterase, adenosine deaminase, and malondialdehyde were increased in CCl4-administered rats, with reduction in both enzymatic and nonenzymatic antioxidant levels. However, pretreatment of rats with AEBP leaves, at tested doses, prevented these changes. Conclusions The increased antioxidant status and the inhibition of acetylcholinesterase activity show that AEBP leaves improve learning memory and stabilizes memory impairment caused by CCl4.


Assuntos
Tetracloreto de Carbono/toxicidade , Kalanchoe , Transtornos da Memória/prevenção & controle , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Adenosina Desaminase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Masculino , Malondialdeído/metabolismo , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Silimarina/farmacologia , Água/química
15.
Klin Padiatr ; 231(5): 262-268, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31505693

RESUMO

OBJECTIVE: The consumption of illegal substances during pregnancy is an increasing social and medical issue. Main substances of prenatal drug exposure are beside tehtrahydrocannabinol (THC), opioids and methamphetamine. The effect of these substances on the long-term development of children remains uncertain. METHODS: Since 2012 newborn infants born at the university hospital of children at Leipzig which were prenatal exposed to drugs were followed long-term at the out-patient clinic for child protection. For 42 children with prenatal opioid or methamphetamine exposure the developmentent was analysed using the Bayley Scales (BSID III) at the age of 2-3 years. The children were compared with 84 unexposed control children. One case matched to 2 controls, adapted by age, gender, gestational age and birth weight. RESULTS: Motoric development between prenatal methylamphetamine, opioid exposed children and the control group showed no significant difference. Methylamphetamine exposed children (n=23) At 2 exposure show significantly lower scores in cognition and language (79,1 compared 95,9 of the control group), opioid exposed children have a slight cognitive deficits with a medium score of 91,7 (n=19). 56% of the methamphetamine group were developmentally retarded at the measurement date. Additionally, children had significant lower Bayley Scores which had single parent and/ or low educational and professional qualifications of their caregiver. Both substances increased the risk of postnatal complications to 46-53% despite of similar gestational ages in all groups. CONCLUSION: Children with prenatal methamphetamine or opioid exposure seem to have cognition and language deficits at 2 and 3 years of age. Methamphetamine might have a higher negative effect than opioids. The psychosocial risk factors associated with parental drug abuse are important for achieving age-appropriate development.


Assuntos
Analgésicos Opioides/toxicidade , Desenvolvimento Infantil/efeitos dos fármacos , Cognição/efeitos dos fármacos , Metanfetamina/toxicidade , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Comportamento do Lactente/efeitos dos fármacos , Comportamento do Lactente/psicologia , Recém-Nascido , Linguagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
16.
Eur Cytokine Netw ; 30(2): 59-66, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486397

RESUMO

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1ß), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1ß, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.


Assuntos
Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Animais , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Interleucina-1beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
17.
Biomed Pharmacother ; 118: 109033, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545235

RESUMO

Studies suggest that abnormal neurodevelopment of prefrontal striatal circuits is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). In the present study, we investigated the effect of catalpol, an active ingredient of Rehmanniae radix preparata, which is the most frequently used Chinese medicinal herb for the treatment of ADHD, on behavior and neurodevelopment in spontaneously hypertensive rats (SHR). SHR were divided into SHR group (vehicle, i.g.), methylphenidate (MPH) group (2 mg/kg/day, i.g.), and catalpol group (50 mg/kg/day i.g.), and Wistar-Kyoto (WKY) rats were used as control group (vehicle, i.g.). Open Field Test (OFT) and Morris water maze (MWM) test were performed to assess the effect of catalpol on behavior. Results revealed that both catalpol and MPH treatment decreased average speed, time spent in the central area, rearing times, and central area visits, increased the immobility time of SHR in OFT, and increased number of visits to the annulus, and time spent in target quadrant in the MWM test. Hematoxylin and eosin (H&E) staining showed that catalpol reduced irregular neuronal arrangement, ruptured nuclear membranes, and resulted in disappearance of the nucleolus in the prefrontal cortex (PFC) and striatum of SHR. Moreover, immuno-fluorescent staining of NeuN and myelin basic protein (MBP) indicated that catalpol ameliorated neuronal loss and contributed to myelination. Finally, western blot and immunostaining analysis suggested that several regulatory proteins involved in PFC development were up-regulated by catalpol treatment, such as brain-derived neurotrophic factor (BDNF), cyclin-dependent kinase 5 (Cdk5), p35, fibroblast growth factor (FGF) 21 and its receptor (FGFR)1. Taken together, catalpol can effectively ameliorate hyperactive and impulsive behavior, improve spatial learning and memory in SHR, likely through the neurodevelopmental pathways. Nonetheless, whether catalpol could attenuate inattention in SHR and the pathway by which catalpol reduces neuronal loss remain to be further studied.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Glucosídeos Iridoides/uso terapêutico , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metilfenidato/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
18.
Bol. latinoam. Caribe plantas med. aromát ; 18(5): 459-479, sept. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-1008268

RESUMO

Neuronal cell damage is often caused by prolonged misuse of Methylphenidate (MPH). Topiramate (TPM) carries neuroprotective properties but its assumed mechanism remains unclear. The present study evaluates in vivo role of various doses of TPM and its mechanism against MPH-induced motor activity and related behavior disorder. Thus, we used domoic acid (DOM), bicuculline (BIC), Ketamine (KET), Yohimibine (YOH) and Haloperidole (HAL) as AMPA/kainite, GABAA, NMDA, ɑ2 adrenergic and D2 of dopamine receptor antagonists respectively. Open Field Test (OFT), Elevated Plus Maze (EPM) and Forced Swim Test (FST) were used to study motor activity, anxiety and depression level. TPM (100 and 120 mg/kg) reduced MPH-induced rise and inhibited MPH-induced promotion in motor activity disturbance, anxiety and depression. Pretreatment of animals with KET, HAL, YOH and BIC inhibited TPM- improves anxiety and depression through the interacting with Dopaminergic, GABAA, NMDA and ɑ2-adrenergic receptors.


El daño a las células neuronales a menudo es causado por el uso prolongado de metilfenidato (MPH). El topiramato (TPM) tiene propiedades neuroprotectoras, pero su mecanismo de acción no es claro. El presente estudio evalúa el papel in vivo de varias dosis de TPM y su mecanismo contra la actividad motora inducida por MPH y el trastorno de comportamiento relacionado. Utilizamos ácido domoico (DOM), bicuculina (BIC), ketamina (KET), yohimbina (YOH) y haloperidol (HAL), así como antagonistas AMPA/kainato, GABAA, NMDA, ɑ2-adrenérgico y D2 dopaminérgicos, respectivamente. Se utilizaron las pruebas de campo abierto (OFT), elevación de laberinto (EPM) y natación forzada (FST) para estudiar la actividad motora, la ansiedad y el nivel de depresión. El TPM (100 y 120 mg/kg) redujo el aumento inducido por MPH e inhibió la promoción inducida por MPH en la alteración de la actividad motora, la ansiedad y la depresión. El tratamiento previo de animales con KET, HAL, YOH y BIC inhibió el TPM, mejora la ansiedad y la depresión a través de la interacción con los receptores dopaminérgicos, GABAA, NMDA y ɑ2-adrenérgico.


Assuntos
Animais , Masculino , Ratos , Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , /farmacologia , Transtornos Mentais/prevenção & controle , Metilfenidato/efeitos adversos , Ratos Wistar , Neurotransmissores/metabolismo , Transtornos Mentais/induzido quimicamente , Atividade Motora/efeitos dos fármacos
19.
J Stroke Cerebrovasc Dis ; 28(11): 104288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31395423

RESUMO

PURPOSE: The present study was to observe the therapeutic efficiency of Clematichinenoside (AR) on cerebral ischemic injury in rats, especially on neurological and motor function recovery and to explore the underlying mechanism. METHODS: Following middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, rats were treated orally with 32, 16, and 8 mg/kg AR respectively for 14 days during which cerebral injury was evaluated and proinflammatory factors tumor necrosis factor-α and interleukin-6 as well as neurotrophic factors brain-derived neurotrophic factor and Neurotrophin-3 levels were determined with ELISA kits. Immunohistochemical analysis on number of neurons and reactive astrocytes in the hippocampus was to demonstrate the effect of AR on neuronal survival. Motor, learning, and memory recovery were assessed by Morris water maze, passive avoidance experiment, and rotatory rod test. Neuroprotection and anti-inflammation-related Notch and nuclear factor-κB (NF-κB) signaling pathways were analyzed by PCR and Western blot techniques on mammalian achaete-scute homologs1, Notch-1, intracellular Notch receptor domain, Jagged-1, transcription factor hairy, enhancer of split1 (Hes1), as well as the nuclear import of NF-κB in hippocampus. RESULTS: AR administration reduced cerebral injury in rats exposed to MCAO/R and after treatment of AR for 14 days, proinflammatory reaction was inhibited, with neuronal survival rate raised and motor function recovery facilitated. PCR and WB analysis of Notch/NF-κB signaling pathway revealed the inhibitory effect of AR on pathway related components. CONCLUSIONS: AR is beneficial to recovery of neurological and motor function in rats after cerebral ischemic injury via inhibiting Notch/NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptor Notch1/metabolismo , Saponinas/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/psicologia , Masculino , Memória/efeitos dos fármacos , Neurotrofina 3/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais
20.
Biomed Pharmacother ; 118: 109276, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377466

RESUMO

BACKGROUND: Paeonia lactiflora (PL) was widely used for pain relief, but its effects on migraine headaches remain unclear. PURPOSE: The aim of the present study was to investigate the effects of PL on migraine headaches. METHODS: First, we found that PL was frequently used in Taiwan for headache treatment based on data from Taiwan's National Health Insurance Research Database. Migraine was induced through the intraperitoneal injection (i.p.) of nitroglycerin (NTG, 10 mg/kg) in rats. Pretreatment with PL was administered orally 30 min prior to the NTG i.p. Migraine headache behavior was observed by video-recordings. Finally, the rats were sacrificed and brain was removed for immunohistochemistry staining analysis. RESULTS: The frequency and total time spent rearing up and sniffing in exploratory behavior, and walking in locomotor behavior, were reduced in the NTG group compared with the control group (all p <  0.001). This reduction could be ameliorated by pretreatment with PL 1.0 g/kg (all p <  0.05). Total time spent in the light chamber was lower in the NTG group compared with the control group (p <  0.05); this could be ameliorated by pretreatment with 1.0 g/kg PL (p <  0.05). The rats in the NTG group spent longer time on the smooth surface than those in the control group (p <  0.001); this could be shortened by pretreatment with 0.5 and 1.0 g/kg PL (both p <  0.01). The traveling distance of rats in the NTG group was shorter than in the control group (p <  0.001); rats given 1.0 g/kg PL had a longer traveling distance than those in the NTG group (p <  0.01). Both c-fos and CGRP immunoreactive cells increased in the TNC in the NTG group compared with that of the control group (both p <  0.001); this increased could be reduced by pretreatment with PL 0.5 and 1.0 g/kg (both p <  0.05). CONCLUSION: Pretreatment with PL ameliorated migraine headache behaviors in the NTG-induced migraine rat model, suggesting pretreatment with PL is beneficial for migraine headache treatment. This effect of PL is related to the decrease of c-fos and CGRP in the TNC. However, still there are too many methodological limitations which need to be overcome in further experiments to support the data.


Assuntos
Comportamento Animal , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Paeonia/química , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Depressão/complicações , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Reação de Congelamento Cataléptica , Asseio Animal , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Imobilização , Masculino , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/fisiopatologia , Atividade Motora/efeitos dos fármacos , Nitroglicerina , Dor/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Sono , Núcleos do Trigêmeo/efeitos dos fármacos , Núcleos do Trigêmeo/patologia , Núcleos do Trigêmeo/fisiopatologia
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