RESUMO
Mephedrone is a representative of synthetic cathinones that is known from its rewarding and psychostimulant effects. It exerts behavioural sensitization after repeated and then interrupted administration. In our study, we investigated a role of the L-arginine-NO-cGMP-dependent signalling in the expression of sensitization to hyperlocomotion evoked by mephedrone. The study was carried out in male albino Swiss mice. The tested mice received mephedrone (2.5 mg/kg) for 5 consecutive days and on the 20th day of the experiment (the 'challenge' day) animals received both mephedrone (2.5 mg/kg) and a given substance that affects the L-arginine-NO-cGMP signalling, that is, L-arginine hydrochloride (125 or 250 mg/kg), 7-nitroindazole (10 or 20 mg/kg), L-NAME (25 or 50 mg/kg) or methylene blue (5 or 10 mg/kg). We observed that 7-nitroindazole, L-NAME and methylene blue inhibited the expression of sensitization to the mephedrone-induced hyperlocomotion. Moreover, we demonstrated that the mephedrone-induced sensitization is accompanied by lowered levels of D1 receptors and NR2B subunits in the hippocampus, whereas a concurrent administration of L-arginine hydrochloride, 7-nitroindazole and L-NAME with the mephedrone challenge dose reversed these effects. Methylene blue only reversed the mephedrone-induced effects on hippocampal levels of the NR2B subunit. Our study confirms that the L-arginine-NO-cGMP pathway contributes to mechanisms underlying the expression of sensitization to the mephedrone-evoked hyperlocomotion.
Assuntos
Azul de Metileno , Óxido Nítrico , Camundongos , Masculino , Animais , NG-Nitroarginina Metil Éster/farmacologia , Azul de Metileno/farmacologia , Óxido Nítrico/metabolismo , Arginina/farmacologia , Locomoção , GMP Cíclico/metabolismoRESUMO
Schizophrenia and depression are heterogeneous disorders. The complex pathomechanism of the diseases imply that medication responses vary across patients. Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. The evidence correlates well with clinical observations, suggesting that new atypical antipsychotic drugs are effective against negative and cognitive symptoms of schizophrenia, as well as against affective symptoms observed in depression. The purpose of this review presents the background and evidence for the use of the new second/third-generation antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) in treatment of schizophrenia and depression. We have first provided a brief overview of the major neurobiological underpinnings of schizophrenia and depression. We then shortly discuss efficacy, safety and limitations of ongoing pharmacotherapy used in depression and schizophrenia. Mainly, we have focused this review on the therapeutic potential of new atypical antipsychotic drugs-currently existing-to be effective in psychotic, as well as in affective disorders.
Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Depressão/tratamento farmacológico , Humanos , Cloridrato de Lurasidona , Psicotrópicos/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológicoRESUMO
The increasing production and use of silver nanoparticles (AgNPs) as antimicrobial agents in medicinal and commercial products creates a substantial risk of exposure, especially for infants and children. Our current knowledge concerning the impact of AgNPs on developing brain is insufficient. Therefore we investigated the temporal profile of transcriptional changes in cellular components of the neurovascular unit in immature rats exposed to a low dose of AgNPs. The behavior of animals under these conditions was also monitored. Significant deposition of AgNPs in brain of exposed rats was identified and found to persist over the post-exposure time. Substantial changes were noted in the transcriptional profile of tight junction proteins such as occludin and claudin-5, and pericyte-related molecules such as angiopoietin-1. Moreover, downregulation of platelet-derived growth factor (PDGFß) and its receptor (PDGFßR) which constitute the main signaling pathway between endothelial cells and pericytes was observed. These were long-lasting effects, accompanied by overexpression of astroglial-specific GFAP mRNA and endothelial cell adhesion molecule, ICAM-1, involved in the pathomechanism of neuroinflammation. The profile of changes indicates that even low doses of AgNPs administered during the early stage of life induce dysregulation of neurovascular unit constituents which may lead to disintegration of the blood-brain barrier. This was confirmed by ultrastructural analysis that revealed enhanced permeability of cerebral microvessels resulting in perivascular edema. Changes in the behavior of exposed rats indicating pro-depressive and anti-anxiety impacts were also identified. The results show a high risk of using AgNPs in medical and consumer products dedicated for infants and children.
Assuntos
Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Angiopoietina-1 , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Claudina-5/farmacologia , Células Endoteliais/metabolismo , Masculino , Nanopartículas Metálicas/química , Microvasos , Ocludina/genética , Permeabilidade , Ratos , Prata/química , Testes de Toxicidade , TranscriptomaRESUMO
Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or ß-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies.
Assuntos
Adenilil Ciclases/metabolismo , Dependência de Morfina/metabolismo , Adenilil Ciclases/genética , Animais , Humanos , Dependência de Morfina/genética , Receptores Opioides/genética , Receptores Opioides/metabolismo , beta-Arrestinas/metabolismoRESUMO
Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki=0.046nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki=0.0224nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki=0.8nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.
Assuntos
Íleo/efeitos dos fármacos , Picolinas/síntese química , Picolinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Sítios de Ligação , Bioensaio , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Estrutura Molecular , Picolinas/química , Ligação Proteica/efeitos dos fármacos , Ratos , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2C de Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.
Assuntos
Benzodioxóis/farmacologia , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Piperidinas/farmacologia , Animais , Ácidos Araquidônicos/metabolismo , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/efeitos adversos , Benzodioxóis/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Endocanabinoides/metabolismo , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Glicerídeos/metabolismo , Hipotermia/induzido quimicamente , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Pirazóis/farmacologia , RimonabantoRESUMO
Novel 1-(1,4-alkylaryldisubstituted-4,5-dihydro-1H-imidazo)-3-substituted urea derivatives have been synthesized and evaluated for their central nervous system activity. Compounds 3a-m were prepared in the reaction between the respective 1-alkyl-4-aryl-4,5-dihydro-1H-imidazol-2-amines 1a-c and appropriate isocyanates 2 in dichloromethane. The compounds were subjected to in silico ADMET studies in order to select best candidates for in vivo experiments. The effects of the compounds on the spontaneous locomotor activity and amphetamine-evoked hyperactivity were estimated. Analgesic activity, without or in the presence of naloxone, was assessed in the writhing test. The tendency to change the HTR, evoked by l-5-HTP and the involvement in alteration in body temperature in mice was studied. Additionally, to check possible occurrence of drug-induced changes in the muscle relaxant activity of mice, which may have contributed to their behaviour in other tests, the rota-rod and chimney tests were performed. The new urea derivatives exerted significant activities in the performed pharmacological tests, although the presented results show a preliminary estimation, and thus, need to be extended for identification and understanding the complete pharmacological profile of the examined compounds.
Assuntos
Analgésicos não Narcóticos/síntese química , Imidazóis/síntese química , Ureia/análogos & derivados , Analgésicos não Narcóticos/farmacologia , Animais , Desenho de Fármacos , Imidazóis/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Receptores Opioides/efeitos dos fármacos , Ureia/farmacologiaRESUMO
The activity of several halogenated copper (II) complexes of 4-chloro-3-nitrophenylthiourea derivatives has been tested against Mycobacterium tuberculosis strains and strains of non-tuberculous mycobacteria. The compounds were 2-16 times more potent than current TB-drugs against multidrug-resistant M. tuberculosis 210. The 3,4-dichlorophenylthiourea complex (5) was equipotent to ethambutol (EMB) towards M. tuberculosis H37Rv and 192 strains. All derivatives acted 2-8 times stronger than isoniazid (INH) against nontuberculous isolates. In the presence of chosen coordinates, the 2-64 times reduction of MIC values of standard drugs was denoted. The synergistic interaction was found between the complex 4 and rifampicin (RMP), and additivity of 1-5, 8 in pairs with EMB and/or streptomycin (SM) against M. tuberculosis 800 was established. All coordination compounds in combination with at least one drug showed additive activity towards both H37Rv and 192 isolates. In 67% incidences of indifference, the individual MIC of a drug decreased 2-16-fold. One can conclude that the novel thiourea chelates described here are potent hits for further developments of new agents against tuberculosis.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Antituberculosos/farmacologia , Cobre , Testes de Sensibilidade Microbiana , Etambutol , Isoniazida/farmacologia , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many new and exciting techniques being developed over the past 5-10 years alone. Drug design and discovery, and the search for new safe and well-tolerated compounds, as well as the ineffectiveness of existing therapies, and society's insufficient knowledge concerning the prophylactics and pharmacotherapy of the most common diseases today, comprise a serious challenge. This can influence not only the quality of human life, but also the health of whole societies, which became evident during the COVID-19 pandemic. In general, the process of drug development consists of three main stages: drug discovery, preclinical development using cell-based and animal models/tests, clinical trials on humans and, finally, forward moving toward the step of obtaining regulatory approval, in order to market the potential drug. In this review, we will attempt to outline the first three most important consecutive phases in drug design and development, based on the experience of three cooperating and complementary academic centers of the Visegrád group; i.e., Medical University of Lublin, Poland, Masaryk University of Brno, Czech Republic, and Comenius University Bratislava, Slovak Republic.
RESUMO
Two polyphenols-hyperoside (HYP) and protocatechuic acid (PCA) were reported to exert antidepressant activity in rodents after acute treatment. Our previous study also showed that this activity might have been influenced by the monoaminergic system and the upregulation of the brain-derived neurotropic factor (BDNF) level. A very long-term pharmacological therapy is required for the treatment of a patient with depression. The repetitive use of antidepressants is recognized to impact the brain structures responsible for regulating both emotional and cognitive behaviors. Thus, we investigated the antidepressant, anxiolytic, and procognitive effects of HYP and PCA in mice after acute and prolonged treatment (14 days). Both polyphenols induced an anxiogenic-like effect after acute treatment, whereas an anxiolytic effect occurred after repetitive administration. PCA and HYP showed procognitive effects when they were administered acutely and chronically, but it seems that their influence on long-term memory was stronger than on short-term memory. In addition, the preset study showed that the dose of 7.5 mg/kg of PCA and HYP was effective in counteracting the effects of co-administered scopolamine in the long-term memory impairment model induced by scopolamine. Our experiments revealed the compounds have no affinity for 5-HT1A and 5-HT2A receptors, whereas a significant increase in serum serotonin level after prolonged administration of PCA and HYP at a dose of 3.75 mg/kg was observed. Thus, it supports the involvement of the serotonergic system in the polyphenol mechanisms. These findings led us to hypothesize that the polyphenols isolated from Impatiens glandulifera can hold promise in treating mental disorders with cognitive dysfunction. Consequently, extended studies are necessary to delve into their pharmacological profile.
RESUMO
This study investigated the influence of sildenafil and methylene blue (MB), two modulators of the nitric oxide (NO)-cyclic guanosine-3',5'-monophosphate (cGMP) pathway on amnesic effects of two benzodiazepines (BZs) (diazepam (DZ) and flunitrazepam (FNZ)), in rodents-mice and rats. In the modified elevated plus maze (mEPM) and novel object recognition (NOR) tests, MB given ip at a dose of 5 mg/kg 5 min prior to DZ administration (0.25 or 1 mg/kg, sc) enhanced/induced memory impairment caused by DZ. When MB (2.5, 5, and 10 mg/kg) was applied 5 min prior to FNZ administration (0.05 and 0.1 mg/kg), an effect was opposite and memory impairment induced by FNZ was reduced. When sildenafil (2.5 and 5 mg/kg, ip) was applied 5 min prior to DZ, we observed a reduction of DZ-induced memory deficiency in the mEPM test. A similar effect of sildenafil was shown in the NOR test when the drug was applied at doses of 1.25, 2.5, and 5 mg/kg prior to DZ. In the mEPM test, sildenafil at abovementioned doses had no effects on FNZ-induced memory impairment. In turns, sildenafil administered at doses of 2.5 and 5 mg/kg increased the effect of FNZ on memory impairment in the NOR test. In conclusion, the NO-cGMP pathway is involved differentially into BZs-induced spatial and recognition memory impairments assessed using the NOR and mEPM tests. Modulators of the NO-cGMP pathway affect animal behavior in these tests in a different way depending on what benzodiazepine is applied.
Assuntos
GMP Cíclico/metabolismo , Diazepam/toxicidade , Flunitrazepam/toxicidade , Óxido Nítrico/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Moduladores GABAérgicos/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/fisiologia , Roedores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Memória Espacial/fisiologiaRESUMO
Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the µ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.
Assuntos
Preparações Farmacêuticas , Receptor 5-HT1A de Serotonina , Analgésicos Opioides/farmacologia , Animais , Camundongos , Simulação de Acoplamento Molecular , DorRESUMO
We have recently demonstrated that the hydroethanolic extracts of Impatiens glandulifera Royle (Balsaminaceae) have antianxiety effect in mice. The present study was aimed to investigate an antidepressant activity of hyperoside (HYP) and protocatechuic acid (PCA), two polyphenols isolated from the aerial parts of this plant, using the forced swimming test (FST) and tail suspension test (TST) in mice. The implication of the monoaminergic system in this effect was assessed and brain-derived neurotrophic factor (BDNF) expression was measured. At doses 1.875, 3.75 and 7.5â¯mg/kg, HYP and PCA significantly reduced immobility in the FST and TST, without affecting locomotor activity of mice. Pretreatment with p-chlorophenylalanine (PCPA 100â¯mg/kg, a serotonin synthesis inhibitor) or α-methyl-DL-tyrosine (AMPT 100â¯mg/kg, a catecholamine synthesis inhibitor) was able to prevent antidepressant-like effect of HYP and PCA (3.75â¯mg/kg). Sub-effective doses of fluoxetine (5â¯mg/kg) or reboxetine (2â¯mg/kg) were capable of potentiating the effect of a sub-effective dose of HYP (0.94â¯mg/kg) in the FST. Co-administration of sub-effective dose of PCA (0.94â¯mg/kg) and reboxetine (2â¯mg/kg) resulted in reducing immobility in the FST. The antidepressant-like effect of HYP and PCA was also prevented by the administration of sulpiride (50â¯mg/kg), a D2 antagonist. In addition, HYP (3.75 and 7.5â¯mg/kg) and PCA (7.5â¯mg/kg) improved the expression of hippocampal BDNF of mice subjected to TST. Altogether, our findings suggest that HYP and PCA exert antidepressant-like effects in mice, which was possibly mediated by monoaminergic system and the upregulation of BDNF level.
Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Depressão/metabolismo , Hidroxibenzoatos/uso terapêutico , Impatiens , Quercetina/análogos & derivados , Animais , Antidepressivos/isolamento & purificação , Antidepressivos/farmacologia , Aminas Biogênicas/biossíntese , Depressão/tratamento farmacológico , Depressão/psicologia , Relação Dose-Resposta a Droga , Hidroxibenzoatos/isolamento & purificação , Hidroxibenzoatos/farmacologia , Masculino , Camundongos , Componentes Aéreos da Planta , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Quercetina/isolamento & purificação , Quercetina/farmacologia , Quercetina/uso terapêutico , Natação/psicologiaRESUMO
Therapy of depression is difficult and still insufficient despite the presence of many antidepressants on the market. Therefore, there is a constant need to search for new, safer, and more effective drugs that could be used in the treatment of depression. Among many methods, chemical modification is an important strategy for new drug development. This study evaluates antidepressant-like effects and possible mechanism of action of two new arylpiperazine derivatives with isonicotinic and picolinic nuclei, compounds 4pN-(3-(4-(piperonyl)piperazin-1-yl)propyl) isonicotinamide and 3oN-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl) picolinamide. The forced swim test (FST) and tail suspension test (TST), as two predictive tests for antidepressant effect in mice, were used. The possible involvement of serotonergic system in the effects of the new compounds in the FST through pharmacological antagonists/modulators of serotonergic transmission was also investigated. Compounds 4p and 3o were shown to possess antidepressant activity in both tests, FST and TST. The antidepressant-like effects of the new compounds in the FST were prevented by pretreatment of mice with pCPA (serotonin depletor), (-)pindolol (mixed 5-HT1A/1B and ß-adrenergic antagonist), and WAY 100635 (selective 5-HT1A antagonist). Additionally, in drug interaction studies, the 5-HT2A/2C antagonist, ketanserin, and the classic antidepressant, imipramine, potentiated antidepressant-like effect of both new compounds. The obtained results demonstrate that the new compounds 4p and 3o produce an antidepressant-like effect in mice which seems to be mediated by interaction with the serotonin 5-HT1A receptors and in the case of 4p, also with the 5-HT2C receptors.
Assuntos
Antidepressivos/farmacologia , Piperazinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Animais , Elevação dos Membros Posteriores , Imipramina/farmacologia , Ketanserina/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Picolinas , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores de Serotonina/fisiologiaRESUMO
The goal of the present study was to examine the effects of N-methyl-aspartate (NMDA) receptor antagonists-memantine and ketamine and the drugs modifying the NO:cGMP pathway-NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), the endogenous precursor of NO-L-arginine, and the guanylyl cyclase inhibitor-methylene blue (MB) on the development of sensitization to withdrawal signs precipitated after chronic, interrupted treatment with diazepam, a benzodiazepine receptor agonist, in mice. To develop the sensitization, the mice were divided into groups: continuously and sporadically (with two diazepam-free periods) treated with diazepam (15 mg/kg, sc). To precipitate the withdrawal syndrome (clonic and tonic seizures, and death), pentylenetetrazole (55 mg/kg, sc) with the benzodiazepine receptor antagonist, flumazenil (5.0 mg/kg, ip), were administered after the last injection of diazepam or saline. Memantine (2.5, 5.0 mg/kg), and ketamine (2.5, 5.0 mg/kg), L-NAME (100, 200 mg/kg) and 7-NI (20 and 40 mg/kg), L-arginine (250, 500 mg/kg) and MB (5 and 10 mg/kg) were administered ip in sporadically diazepam-treated mice during the diazepam-free periods. Our results indicated that both NMDA receptor antagonists and drugs that inhibit the NO:cGMP pathway, except L-arginine (the endogenous donor of NO), attenuated the diazepam-induced sensitization to withdrawal signs in mice. Thus, NMDA receptors and the NO:cGMP pathway are involved in the mechanisms of sensitization to benzodiazepine withdrawal.
Assuntos
Diazepam/farmacologia , Pentilenotetrazol/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Benzodiazepinas/farmacologia , GMP Cíclico/metabolismo , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
The widespread use of silver nanoparticles (AgNPs) in medicine and in multiple commercial products has motivated researchers to investigate their potentially hazardous effects in organisms. Since AgNPs may easily enter the brain through the blood-brain barrier (BBB), characterization of their interactions with cellular components of the neurovascular unit (NVU) is of particular importance. Therefore, in an animal model of prolonged low-dose exposure, we investigate the extent and mechanisms of influence of AgNPs on cerebral microvessels. Adult rats were treated orally with small (10â¯nm) AgNPs in a dose of 0.2â¯mg/kg b.w. over a 2-week period. A silver citrate-exposed group was established as a positive control of ionic silver effects. Alterations in the expression of tight junction proteins claudin-5, ZO-1, and occludin, were observed. These effects are accompanied by ultrastructural features indicating enhanced permeability of microvessels such as focal edema of perivascular astrocytic processes and surrounding neuropil. We did not identify changes in the expression of PDGFßR which is a marker of pericytes. Ultrastructural alterations in these cells were not identified. The results show that altered integrity of cerebral vessels under a low-dose of AgNP-exposure may be the consequence of dysfunction of endothelial cells caused by disruption of tight junction proteins.
Assuntos
Encéfalo/irrigação sanguínea , Capilares/efeitos dos fármacos , Citratos/toxicidade , Nanopartículas Metálicas/toxicidade , Compostos de Prata/toxicidade , Administração Oral , Animais , Capilares/metabolismo , Capilares/ultraestrutura , Permeabilidade Capilar/efeitos dos fármacos , Citratos/administração & dosagem , Claudina-5/genética , Claudina-5/metabolismo , Relação Dose-Resposta a Droga , Masculino , Ocludina/genética , Ocludina/metabolismo , Tamanho da Partícula , Ratos Wistar , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Compostos de Prata/administração & dosagem , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/ultraestrutura , Fatores de Tempo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
The goal of the study was to investigate the effects of drugs modifying L-arginine:NO:cGMP pathway on the development of tolerance to flunitrazepam (FNZ)-induced motor impairment in mice. FNZ-induced motor incoordination was assessed on the 1st and 8th days of experiment, using the rotarod and chimney tests. It was found that (a) both a non-selective nitric oxide synthase (NOS) inhibitor: N G-nitro-L-arginine methyl ester (L-NAME) and an unselective neuronal NOS inhibitor: 7-nitroindazole (7-NI) inhibited the development of tolerance to the motor-impairing effects of FNZ in the rotarod and the chimney tests and (b) both a NO precursor: L-arginine and a selective inhibitor of phosphodiesterase 5 (PDE5): sildenafil did not affect the development of tolerance to FNZ-induced motor impairment in mice. Those findings provided behavioural evidence that NO could contribute an important role in the development of tolerance to FNZ in mice.
Assuntos
Arginina/farmacologia , Tolerância a Medicamentos/fisiologia , Flunitrazepam/farmacologia , Óxido Nítrico/fisiologia , Transdução de Sinais/fisiologia , Animais , GMP Cíclico/fisiologia , Interações Medicamentosas , Indazóis/farmacologia , Masculino , Camundongos , Destreza Motora/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila/farmacologiaRESUMO
BACKGROUND: The present study was undertaken to better understand possible interaction(s) between a non-selective nitric oxide inhibitor: N(G)-nitro-l-arginine methyl ester (l-NAME) and benzodiazepines (BZs) in recognition memory. METHODS: The study was carried out on adult male albino Wistar rats. A novel object recognition (NOR) task was used to evaluate memory process. RESULTS: Combined administration of l-NAME (50mg/kg, ip) with a threshold dose of DZ (0.25mg/kg) induced amnesic effects in rats, participating in the NOR test. On the other hand, following a combined administration of l-NAME (100mg/kg, ip) with flunitrazepam (FNZ; 0.1mg/kg), it was found out that l-NAME inhibited the amnesic effects of FNZ on rats in the NOR test. CONCLUSIONS: The obtained results suggest that suppressed NO synthesis may lead to a facilitation of DZ-induced memory impairment but surprisingly may prevent amnesic effect after FNZ in rats, submitted to NOR task.
Assuntos
Diazepam/farmacologia , Flunitrazepam/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , RatosRESUMO
The goal of the study was to investigate the effects of ketamine and memantine on the development and expression of tolerance to diazepam (DZ)-induced motor impairment in mice. DZ-induced motor incoordination was assessed by the rotarod and chimney tests. It was found that (a) ketamine, at the dose of 5mg/kg (but not 2.5mg/kg), decreased the expression, but not the development, of tolerance to the motor impairing effects of DZ, (b) memantine, at the doses of 5 and 10mg/kg decreased both the development and expression of DZ tolerance in the rotarod test (also in the chimney test but at the higher dose of 10mg/kg) and (c) ketamine and memantine alone had no effect, either in the rotarod or the chimney test in mice. Those findings provided behavioral evidence that the glutamatergic system could contribute an important role in the development and/or expression of tolerance to DZ in mice.
Assuntos
Adaptação Fisiológica , Diazepam/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Ketamina/farmacologia , Memantina/farmacologia , CamundongosRESUMO
Nanoscale particles have large surface to volume ratio that significantly enhances their chemical and biological reactivity. Although general toxicity of nano silver (nanoAg) has been intensively studied in both in vitro and in vivo models, its neurotoxic effects are poorly known, especially those of low-dose exposure. In the present study we assess whether oral administration of nanoAg influences behavior of exposed rats and induces changes in cerebral myelin. We examine the effect of prolonged exposure of adult rats to small (10nm) citrate-stabilized nanoAg particles at a low dose of 0.2mg/kg b.w. (as opposed to the ionic silver) in a comprehensive behavioral analysis. Myelin ultrastructure and the expression of myelin-specific proteins are also investigated. The present study reveals slight differences with respect to behavioral effects of Ag(+)- but not nanoAg-treated rats. A weak depressive effect and hyperalgesia were observed after Ag(+) exposure whereas administration of nanoAg was found to specifically increase body weight and body temperature of animals. Both nanoAg and Ag(+) induce morphological disturbances in myelin sheaths and alter the expression of myelin-specific proteins CNP, MAG and MOG. These results suggest that the CNS may be a target of low-level toxicity of nanoAg.