RESUMO
Gabapentin as an anticonvulsant drug also has beneficial effects in treatment of depression. Previously, we showed that acute administration of gabapentin produced an antidepressant-like effect in the mouse forced swimming test (FST) by a mechanism that involves the inhibition of nitric oxide (NO). Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (KATP), in the present study we investigated the involvement of KATP channels in antidepressant-like effect of gabapentin. Gabapentin at different doses (5-10 mg/kg) and fluoxetine (20 mg/kg) were administrated by intraperitoneal route, 60 and 30 min, respectively, before the test. To clarify the probable involvement of KATP channels, mice were pretreated with KATP channel inhibitor or opener. Gabapentin at dose 10 mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20 mg/kg). Co-administration of subeffective dose (1 mg/kg) of glibenclamide (inhibitor of KATP channels) with gabapentin (3 mg/kg) showed a synergistic antidepressant-like effect. Also, subeffective dose of cromakalim (opener of KATP channels, 0.1 mg/kg) inhibited the antidepressant-like effect of gabapentin (10 mg/kg). None of the treatments had any impact on the locomotor movement. Our study, for the first time, revealed that antidepressant-like effect of gabapentin in mice is mediated by blocking the KATP channels.
Assuntos
Aminas/farmacologia , Antidepressivos/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Canais KATP/metabolismo , Natação , Ácido gama-Aminobutírico/farmacologia , Aminas/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/psicologia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Gabapentina , Resposta de Imobilidade Tônica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Natação/psicologia , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.
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Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Naltrexona/administração & dosagem , Naltrexona/uso terapêutico , Óxido Nítrico/metabolismo , Animais , Interações Medicamentosas , Encefalopatia Hepática/sangue , Encefalopatia Hepática/induzido quimicamente , Lipopolissacarídeos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/uso terapêutico , Nitratos/sangue , Nitritos/sangue , RatosRESUMO
Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10-100mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3mg/kg), while the inducible NOS inhibitor, aminoguanidine (100mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60mg/kg) blunted the anticonvulsant effect of DM (100mg/kg). Also, NMDA antagonists, ketamine (0.5mg/kg) and MK-801 (0.05mg/kg), augmented the anticonvulsant effect of DM (3mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors.
Assuntos
Dextrometorfano/uso terapêutico , Óxido Nítrico/metabolismo , Pentilenotetrazol/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Dextrometorfano/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Masculino , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/induzido quimicamente , Resultado do TratamentoRESUMO
Spinal cord injury (SCI) has a number of severe and disabling consequences including chronic pain. Approximately 40% of patients experience neuropathic pain, which appears to be persistent. Previous studies have demonstrated the neuroprotective effects of magnesium sulfate (MgSO4). We aimed to investigate the effect of MgSO4 on neuropathic pains following SCI in male rats. Thirty-two adult male rats (weight 300-350 g) were used. After laminectomy, a complete SCI was induced by compression of the spinal cord for 1 min with an aneurysm clip. A single dose of 300 or 600 mg/kg MgSO4 was injected intraperitoneally. Tail-flick latency and acetone drop test scores were evaluated before surgery and once a week for 4 weeks after surgery. Rats in groups SCI+Mg300 and SCI+Mg600 showed significantly higher mean tail-flick latencies and lower mean scores in the acetone test compared with those in the SCI+veh group 4 weeks after surgery (P<0.05). These findings revealed that systemic single-dose administration of MgSO4 can attenuate thermal hyperalgesia and cold allodynia induced by SCI in rats.
Assuntos
Analgésicos/farmacologia , Sulfato de Magnésio/farmacologia , Neuralgia/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Analgésicos/administração & dosagem , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Sulfato de Magnésio/administração & dosagem , Masculino , Neuralgia/etiologia , Ratos , Traumatismos da Medula Espinal/complicaçõesRESUMO
CONTEXT: Omega-3 fatty acids have been recently proposed to induce neural improvement in patients with spinal cord injury (SCI) while affecting some hormones including leptin and adiponectin. OBJECTIVES: We tried to evaluate the effect of omega-3 fatty acids on circulatory concentrations of leptin and adiponectin among these patients. DESIGN: This study is a double-blinded randomized clinical trial with intervention duration of 14 months. SETTING: A tertiary rehabilitation center. PARTICIPANTS: Total of 104 patients with SCI who did not meet our exclusion criteria entered the study. Those with history of diabetes, cancer, endocrinology disease, acute infection, and use of special medications were excluded. Patients were divided randomly into the treatment and control group by using permuted balanced block randomization. INTERVENTION: The treatment group received two MorDHA® capsules per day (each capsule contain 465 mg of docosahexaenoic acid (DHA) and 63 mg of eicosapentaenoic acid (EPA)) for 14 months while the control group received placebo capsules with similar color, shape, and taste. MAIN OUTCOMES MEASURES: Leptin and adiponectin concentrations in plasma were measured at the beginning of trial and then after 6 and 14 months. RESULTS: Fourteen months of treatment with DHA and EPA did not influence concentrations of leptin but adiponectin level was significantly decreased (P: 0.03). Weight was positively correlated with leptin level at stage 0 of trial (P: 0.008, r=0.41) while this association was attenuated through stages of trial after intervention. CONCLUSION: Our data show that omega-3 fatty acids may not affect plasma concentrations of leptin but adiponectin level is decreased in patients with SCI. Moreover, this intervention influences the linear relationship between weight and leptin after 14 months administration of DHA and EPA.
Assuntos
Adiponectina/sangue , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Leptina/sangue , Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/tratamento farmacológico , Adolescente , Adulto , Idoso , Ácidos Docosa-Hexaenoicos/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Nowadays, scientific findings in the field of regeneration of nervous system have revealed the possibility of stem cell based therapies for damaged brain tissue related disorders like stroke. Furthermore, to achieve desirable outcomes from cellular therapies, one needs to monitor the migration, engraftment, viability, and also functional fate of transplanted stem cells. Magnetic resonance imaging is an extremely versatile technique for this purpose, which has been broadly used to study stroke and assessment of therapeutic role of stem cells. In this review we searched in PubMed search engine by using following keywords; "Stem Cells", "Cell Tracking", "Stroke", "Stem Cell Transplantation", "Nanoparticles", and "Magnetic Resonance Imaging" as entry terms and based on the mentioned key words, the search period was set from 1976 to 2012. The main purpose of this article is describing various advantages of molecular and magnetic resonance imaging of stem cells, with focus on translation of stem cell research to clinical research.
RESUMO
Cell manufacturing for clinical applications is a unique form of biologics manufacturing that relies on maintenance of stringent work practices designed to ensure product consistency and prevent contamination by microorganisms or by another patient's cells. More extensive, prolonged laboratory processes involve greater risk of complications and possibly adverse events for the recipient, and so the need for control is correspondingly greater. To minimize the associate risks of cell manufacturing adhering to international quality standards is critical. Current good tissue practice (cGTP) and current good manufacturing practice (cGMP) are examples of general standards that draw a baseline for cell manufacturing facilities. In recent years, stem cell researches have found great public interest in Iran and different cell therapy projects have been started in country. In this review we described the role of our tissue banking experiences in establishing a new cGMP cell manufacturing facility. The authors concluded that, tissue banks and tissue banking experts can broaden their roles from preparing tissue grafts to manufacturing cell and tissue engineered products for translational researches and phase I clinical trials. Also they can collaborate with cell processing laboratories to develop SOPs, implement quality management system, and design cGMP facilities.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/normas , Bancos de Tecidos/normas , Animais , Humanos , Irã (Geográfico) , Laboratórios , Controle de QualidadeRESUMO
Clinical grade cultivation of human schwann cell by the utilization of human autologous serum instead of fetal bovine serum, and also avoiding any growth factors, can increase safety level of this procedure in cases of clinical cell transplantation. The aim of this study was demonstration of the feasibility of clinical grade schwann cell cultivation. In this experimental study after obtaining consent from close relatives we harvested 10 sural nerves from brain death donors and then cultured in 10 seperated culture media plus autologous serum. We also prepared autologous serum from donor's whole blood. Then cultured cells were evaluated by S100 antibody staining for both morphology and purity. Cell purity range was from 97% to 99% (mean=98.11 ± 0.782%). Mean of the cell count was 14,055.56 ± 2,480.479 per micro liter. There was not significant correlation between cell purity and either the culture period or the age of donors (P>0.05). The spearman correlation coefficient for the cell purity with the period or the age of donors was 0.21 and 0.09, respectively. We demonstrated the feasibility of clinical grade schwann cell cultivation by the using of human autologous serum instead of fetal bovine serum and also without the using of growth factors. We also recommended all cell preparation facilities to adhere to the GMP and other similar quality disciplines especially in the preparation of clinically-used cell products.
Assuntos
Técnicas de Cultura de Células/métodos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Soro/metabolismo , Adulto , Animais , Bovinos , Células Cultivadas , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas S100/metabolismo , Células de Schwann/metabolismo , Coloração e Rotulagem , Nervo Sural/efeitos dos fármacos , Nervo Sural/transplante , Doadores de TecidosRESUMO
It has been predicted that one of the greatest increase in prevalence of diabetes will happen in the Middle East bear in the next decades. The aim of standard therapeutic strategies for diabetes is better control of complications. In contrast, some new strategies like cell and gene therapy have aimed to cure the disease. In recent years, significant progress has occurred in beta-cell replacement therapies with a progressive improvement of short-term and long term outcomes. In year 2005, considering the impact of the disease in Iran and the promising results of the Edmonton protocol, the funding for establishing a current Good Manufacturing Practice (cGMP) islet processing facility by Endocrinology and Metabolism Research Center was approved by Tehran University of Medical Sciences. Several islet isolations were performed following establishment of cGMP facility and recruitment of all required equipments for process validation and experimental purpose. Finally the first successful clinical islet isolation and transplantation was performed in September 2010. In spite of a high cost of the procedure it is considered beneficial and may prevent long term complications and the costs associated with secondary cares. In this article we will briefly describe our experience in setting up a cGMP islet processing facility which can provide valuable information for regional countries interested to establish similar facilities.
Assuntos
Fiscalização e Controle de Instalações , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Bancos de Tecidos/normas , Humanos , Irã (Geográfico) , Ilhotas Pancreáticas/citologiaRESUMO
The importance of tissue engineering has been established as a promising approach in treating neurodegenerative diseases. The purpose of the current study is to determine the effect of fibrin hydrogel on the differentiation of iPSC into oligodendrocyte. For this purpose, iPSCs transduced by miR-338 expressing lentiviruses. They were treated with basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF)-AA. The process was traced by a 6-day treatment in a mitogen-free medium. At the end of the process, multipolar preoligodendrocytes appeared. In comparison to tissue culture plate (TCP), MTT assay demonstrated a significant increase in the viability of cells cultured in fibrin hydrogel. SEM analysis showed cells with elongated morphology and intertwined intercellular interactions. An immunofluorescent assay confirmed the expression of oligodendrocyte markers Olig2 and O4. In comparison to TCP, real-time PCR data indicated a significant increase in the expression of some markers such as Olig2, MBP, Sox10, and PDGFRα on cells encapsulated in fibrin hydrogel. Overall, the results suggest that fibrin hydrogel improves viability of cells and promotes the differentiation of iPSCs into preoligodendrocytes. Hence, it can be used as an appropriate option in the tissue engineering in order to treat neurodegenerative diseases. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:192-200, 2020.
Assuntos
Diferenciação Celular , Fibrina/química , Hidrogéis/química , Células-Tronco Pluripotentes Induzidas/metabolismo , Oligodendroglia/metabolismo , Alicerces Teciduais/química , Linhagem Celular , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Oligodendroglia/citologiaRESUMO
BACKGROUND: Thalidomide is a sedative/hypnotic agent that is currently used to treat patients suffering from multiple myeloma, myelodysplastic syndromes and erythema nodosum leprosum. Although previous studies have demonstrated that thalidomide possesses anti-depressant-like properties, the exact mechanism that thalidomide exerts this effect is not understood. In this study, we used two mouse models of depression and investigated the possible role of nitric oxide (NO), NO synthase (NOS) and inducible NOS (iNOS) in the ant-depressant-like effects of thalidomide. METHODS: Male mice were injected with different doses of thalidomide intraperitoneally. In order to assess the anti-depressant-like properties of thalidomide, the immobility time of mice was assessed in the forced swimming test (FST) and tail suspension test (TST). Locomotor activity was assessed using the open-field test. To assess the role of nitric oxide, N(G)-nitro-L-arginine methyl ester (L-NAME, non-specific NOS inhibitor), aminoguanidine (selective iNOS inhibitor) or L-arginine (NO precursor) were administered intraperitoneally along with specific doses of thalidomide. RESULTS: Thalidomide (10â¯mg/kg) significantly reduced immobility time in FST and TST. Aminoguanidine (50â¯mg/kg) and L-NAME (10â¯mg/kg) significantly augmented the anti-immobility effects of thalidomide (5â¯mg/kg). L-arginine (750â¯mg/kg) significantly inhibited the anti-immobility effects of thalidomide (10â¯mg/kg). None of the treatment groups demonstrated alteration of locomotor activity. CONCLUSION: Thalidomide exerts its anti-depressant-like effects through a mechanism dependent upon NO inhibition.
Assuntos
Antidepressivos/farmacologia , Óxido Nítrico/metabolismo , Talidomida/farmacologia , Animais , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Locomoção/efeitos dos fármacos , Redes e Vias Metabólicas , Camundongos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
BACKGROUND: Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action. METHODS: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4min was evaluated. All drugs were given intraperitoneally (ip). RESULTS: Selegiline (10mg/kg) decreased the immobility time in the FST similar to fluoxetine (20mg/kg). Pretreatment with l-arginine (NO precursor, 750mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents. CONCLUSIONS: It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.
Assuntos
Antidepressivos/farmacologia , GMP Cíclico/metabolismo , Resposta de Imobilidade Tônica/efeitos dos fármacos , Óxido Nítrico/metabolismo , Selegilina/farmacologia , Natação , Animais , Arginina/farmacologia , Sinergismo Farmacológico , Fluoxetina/farmacologia , Guanidinas/farmacologia , Hipocampo/metabolismo , Indazóis/farmacologia , Masculino , Azul de Metileno/farmacologia , Camundongos , Atividade Motora/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Nitritos/metabolismo , Córtex Pré-Frontal/metabolismo , Selegilina/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila/farmacologiaRESUMO
Lithium is still the main agent in the management of mood disorders such as depression. Likewise, agmatine protects the central nervous system (CNS) against depression. The aim of the present study was to examine the possible additive antidepressant-like effect of agmatine and lithium in mice forced swim test (FST) as well as exploration of the probable involvement of nitric oxide (NO) pathway in this response. Results showed that pretreatment with a subeffective dose of agmatine (0.01â¯mg/kg) augmented the antidepressant-like effect of lithium subeffective dose (3â¯mg/kg) (Pâ¯<â¯0.001). L-NG-nitroarginine methyl ester (L-NAME, nonspecific nitric oxide synthase [NOS] inhibitor) at doses of 10 and 30â¯mg/kg, and 7-nitroindazole (7-NI, neuronal NOS inhibitor) at doses of 15 and 30â¯mg/kg potentiated the antidepressant-like effect of the subeffective combination of lithium (3â¯mg/kg) and agmatine (0.001â¯mg/kg) (Pâ¯<â¯0.001, Pâ¯<â¯0.01, respectively). However, various doses of aminoguanidine (25 and 50â¯mg/kg, inducible NOS inhibitor) failed to alter the immobility time of the same combination (Pâ¯>â¯0.05). Moreover, pretreatment with subeffective doses of L-arginine (substrate for NOS, 300 and 750â¯mg/kg) reversed the augmenting antidepressant-like effect of agmatine (0.01â¯mg/kg) on lithium (3â¯mg/kg) (Pâ¯<â¯0.001). Our results revealed that agmatine enhances the antidepressant-like effects of lithium and the NO pathway might mediate this phenomenon. In addition, constitutive NOS plays a dramatic role in this response.
Assuntos
Agmatina/farmacologia , Antidepressivos/farmacologia , Compostos de Lítio/farmacologia , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Arginina/farmacologia , Quimioterapia Combinada , Guanidinas/farmacologia , Indazóis/farmacologia , Masculino , Camundongos , Transtornos do Humor/tratamento farmacológico , NG-Nitroarginina Metil Éster/farmacologia , Natação/fisiologiaRESUMO
Clinical use of vincristine (VCR), an effective chemotherapeutic agent, has been limited due to its peripheral neuropathy toxicity. Sumatriptan, which is an anti-migraine agent is a specific agonist for 5-hydroxytryptamine 1B, 1D (5HT1B, 1D) receptors. Several studies have shown that sumatriptan exerts anti-inflammatory and immunomodulatory properties. This study aimed to investigate the effects of sumatriptan on VCR-induced peripheral neuropathy in a rat model. Male Wistar rats were intraperitoneally injected with VCR and normal saline four times per week for 2 weeks. In the treatment group, sumatriptan (1â¯mg/kg) was administered intraperitoneally 30â¯min prior to VCR injection every day. Mortality rate, weight variations and histopathological changes were monitored. Hot plate, tail flick and motor nerve conduction velocity (MNCV) tests were used to evaluate sensory and motor neuropathy. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß) and caspase-3 in the dorsal ganglion root were assessed by quantitative reverse transcription-PCR (qRT-PCR). Moreover, the protein levels of p65 nuclear factor kappa B (NF-
Assuntos
Modelos Animais de Doenças , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Sumatriptana/uso terapêutico , Vincristina/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêuticoRESUMO
Glioblastoma multiform (GBM) is a primary malignant brain tumor with a few therapeutic targets available for it. The interaction between the immune system and glioma is an important factor that could lead to novel therapeutic approaches to fight glioma. In this study, we investigated in vitro anti-inflammatory and apoptotic activity of atorvastatin in different concentrations 1, 5, and 10 µM on glioma spheroid cells cultured in a three-dimensional model in fibrin gel that indicate the complex in vivo microenvironment better than a simple two-dimensional cell culture. A mechanistic insight into the role of IL-17RA, TRAF3IP2, and apoptotic genes in progression of glioma could provide an important way for therapy of malignant tumors with manipulation of this inflammatory axis. To reach for these aims, after 24 and 48 h exposure with different concentrations of atorvastatin, caspase-8, caspase-3, Bcl-2, TRAF3IP2, and IL-17RA gene expression were assayed. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cell cycle assay were used for evaluating the cell apoptosis and proliferation. The results showed that atorvastatin has anti-inflammatory and apoptotic effects against glioma spheroids. Atorvastatin induced the expression of caspase-3 and caspase-8 and downregulated the expression of Bcl-2, TRAF3IP2, and IL-17RA especially at 10 µM concentration. These effects are dose dependent. The most likely mechanisms are the inhibition of inflammation by IL-17RA interaction with TRAF3IP2 and NF-κB signaling pathway. Finally, these results suggest that atorvastatin could be used as an anti-cancer agent for glioblastoma treatment.
Assuntos
Anti-Inflamatórios/farmacologia , Atorvastatina/farmacologia , Neoplasias Encefálicas/metabolismo , Técnicas de Cultura de Células/métodos , Glioblastoma/metabolismo , Mediadores da Inflamação/metabolismo , Esferoides Celulares/metabolismo , Anti-Inflamatórios/uso terapêutico , Atorvastatina/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células , Relação Dose-Resposta a Droga , Glioblastoma/tratamento farmacológico , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Esferoides Celulares/efeitos dos fármacos , Resultado do TratamentoRESUMO
Purpose: Glioblastoma multiform (GBM) is the most aggressive glial neoplasm. Researchers have exploited the fact that GBMs are highly vascularized tumors. Anti-angiogenic strategies including those targeting VEGF pathway have been emerged for treatment of GBM. Previously, we reported the anti-inflammatory effect of atorvastatin on GBM cells. In this study, we investigated the anti-angiogenesis and apoptotic activity of atorvastatin on GBM cells. Methods: Different concentrations of atorvastatin (1, 5, 10µM) were used on engineered three-dimensional (3D) human tumor models using glioma spheroids and Human Umbilical Vein Endothelial cells (HUVECs) in fibrin gel as tumor models. To reach for these aims, angiogenesis as tube-like structures sprouting of HUVECs were observed after 24 hour treatment with different concentrations of atorvastatin into the 3-D fibrin matrix and we focused on it by angiogenesis antibody array. After 48 hours exposing with different concentrations of atorvastatin, cell migration of HUVECs were investigated. After 24 and 48 hours exposing with different concentrations of atorvastatin VEGF, CD31, caspase-3 and Bcl-2 genes expression by real time PCR were assayed. Results: The results showed that atorvastatin has potent anti-angiogenic effect and apoptosis inducing effect against glioma spheroids. Atorvastatin down-regulated the expression of VEGF, CD31 and Bcl-2, and induced the expression of caspase-3 especially at 10µM concentration. These effects are dose dependent. Conclusion: These results suggest that this biomimetic model with fibrin may provide a vastly applicable 3D culture system to study the effect of anti-cancer drugs such as atorvastatin on tumor malignancy in vitro and in vivo and atorvastatin could be used as agent for glioblastoma treatment.
Assuntos
Inibidores da Angiogênese/farmacologia , Atorvastatina/farmacologia , Fibrina/química , Glioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana/patologia , Neovascularização Patológica/prevenção & controle , Esferoides Celulares/patologia , Anticolesterolemiantes/farmacologia , Técnicas de Cultura de Células , Movimento Celular , Células Cultivadas , Géis/química , Glioblastoma/irrigação sanguínea , Glioblastoma/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Técnicas In Vitro , Esferoides Celulares/efeitos dos fármacosRESUMO
Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Tramadol/farmacologia , Animais , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Sulfato de Magnésio/farmacologia , Masculino , Camundongos , N-Metilaspartato/farmacologia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , NataçãoRESUMO
Depression is one the world leading global burdens leading to various comorbidities. Lithium as a mainstay in the treatment of depression is still considered gold standard treatment. Similar to lithium another agent agmatine has also central protective role against depression. Since, both agmatine and lithium modulate various effects through interaction with NMDA receptor, therefore, in current study we aimed to investigate the synergistic antidepressant-like effect of agmatine with lithium in mouse force swimming test. Also to know whether if such effect is due to interaction with NMDA receptor. In our present study we found that when potent dose of lithium (30mg/kg) was administered, it significantly decreased the immobility time. Also, when subeffective dose of agmatine (0.01mg/kg) was coadministered with subeffective dose of lithium (3mg/kg), it potentiated the antidepressant-like effect of subeffective dose of lithium. For the involvement of NMDA receptor in such effect, we administered NMDA receptor antagonist MK-801 (0.05mg/kg) with a combination of subeffective dose of lithium (3mg/kg) and agmatine (0.001mg/kg). A significant antidepressant-like effect was observed. Furthermore, when subeffective dose (50 and 75mg/kg) of NMDA was given it inhibited the synergistic effect of agmatine (0.01mg/kg) with lithium (3mg/kg). Hence, our finding demonstrate that agmatine have synergistic effect with lithium which is mediated by NMDA receptor pathway.
Assuntos
Agmatina/farmacologia , Antidepressivos/farmacologia , Lítio/farmacologia , N-Metilaspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Natação/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Lítio/administração & dosagem , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Depression is a devastating disorder which has a high impact on the wellbeing of overall society. As such, need for innovative therapeutic agents are always there. Most of the researchers focused on N-methyl-d-aspartate receptor to explore the antidepressant like activity of new therapeutic agents. Dextromethorphan is a cough suppressant agent with potential antidepressant activity reported in mouse force swimming test. Considering N-methyl-d-aspartate as a forefront in exploring antidepressant agents, here we focused to unpin the antidepressant mechanism of dextromethorphan targeting N-methyl-d-aspartate receptor induced nitric oxide-cyclic guanosine monophosphate signaling. Dextromethorphan administered at a dose of 10 and 30mg/kg i.p significantly reduced the immobility time. Interestingly, this effect of drug (30mg/kg) was inhibited when the animals were pretreated either with N-methyl-d-aspartate (75mg/kg), or l-arginine (750mg/kg) as a nitric oxide precursor and/or sildenafil (5mg/kg) as a phosphodiesterase 5 inhibitor. However, the antidepressant effect of Dextromethorphan subeffective dose (3mg/kg) was augmented when the animals were administered with either L-NG-Nitroarginine methyl ester (10mg/kg) non-specific nitric oxide synthase inhibitor, 7-Nitroindazole (30mg/kg) specific neural nitric oxide synthase inhibitor, MK-801 (0.05mg/kg) an N-methyl-d-aspartate receptor antagonist but not aminoguanidine (50mg/kg) which is specific inducible nitric oxide synthase inhibitor as compared to the drugs when administered alone. No remarkable effect on locomotor activity was observed during open field test when the drugs were administered at the above mentioned doses. Therefore, it is evident that the antidepressant like effect of Dextromethorphan is owed due to its inhibitory effect on N-methyl-d-aspartate receptor and NO- Cyclic guanosine monophosphate pathway.
Assuntos
Antidepressivos/farmacologia , GMP Cíclico/metabolismo , Dextrometorfano/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Óxido Nítrico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Elevação dos Membros Posteriores , Masculino , Camundongos , Atividade Motora , Receptores de N-Metil-D-Aspartato/genética , NataçãoRESUMO
BACKGROUND: Chloroquine (CQ) evokes itch in human and scratching behavior in rodents through a histamine-independent pathway. Chloroquine directly excites peripheral sensory neurons which convey itch signals to the central nervous system. It has been revealed that ATP-sensitive potassium channels (KATP channels) are important in regulating neuronal excitability. Thus, we aimed to investigate the involvement of KATP channels in CQ-induced itch which may also reveal a linkage between metabolic state of cells and itch. METHODS: Intradermal (id) injection of CQ at dose of 400µg/site induces the scratching behavior. KATP channel openers, diazoxide (DZX) and minoxidil (MIN), and a KATP channel blocker, glibenclamide (GLI), were administered intraperitoneally (ip) before CQ. Then the behavior was recorded for 30min, in an unmanned condition, and the scratching bouts were counted by an expert observer who was blinded to the experiments. Furthermore, quantitative reverse transcription-PCR (qRT-PCR) was used to investigate the possible changes in dermal expression of Kcnj8 and Kcnj11, the genes encoding the KATP channels. RESULTS: Our results show that either DZX (10mg/kg, ip) or MIN (10mg/kg, ip) significantly attenuated CQ-induced scratching behavior in mice. Moreover, pretreatment with GLI (3mg/kg, ip) significantly reversed the anti-pruritic effects of DZX and MIN. Our finding of qRT-PCR analysis also show that the expression of Kcnj8 is decreased after CQ injection. CONCLUSIONS: We suggest that KATP channels are possibly involved in CQ-induced itch. While, further studies will be significant to better elucidate the association of metabolic state of cells and itch.