RESUMO
Alzheimer's disease (AD) is a neurodegenerative pathology characterized by progressive impairment of memory, associated with neurochemical alterations and limited therapy. The aim of this study was to evaluate the effects of inosine on memory, neuroinflammatory cytokines, neurotrophic factors, expression of purinergic receptors, and morphological changes in the hippocampus and cerebral cortex of the rats with AD induced by streptozotocin (STZ). Male rats were divided into four groups: I, control; II, STZ; III, STZ plus inosine (50 mg/kg); and IV, STZ plus inosine (100 mg/kg). The animals received intracerebroventricular injections of STZ or buffer. Three days after the surgical procedure, animals were treated with inosine (50 mg/kg or 100 mg/kg) for 25 days. Inosine was able to prevent memory deficits and decreased the immunoreactivity of the brain A2A adenosine receptor induced by STZ. Inosine also increased the levels of brain anti-inflammatory cytokines (IL-4 and IL-10) and the expression of brain-derived neurotrophic factor and its receptor. Changes induced by STZ in the molecular layer of the hippocampus were attenuated by treatment with inosine. Inosine also protected against the reduction of immunoreactivity for synaptophysin induced by STZ in CA3 hippocampus region. However, inosine did not prevent the increase in GFAP in animals exposed to STZ. In conclusion, our findings suggest that inosine has therapeutic potential for AD through the modulation of different brain mechanisms involved in neuroprotection.
Assuntos
Doença de Alzheimer , Inosina , Receptores Purinérgicos , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Inosina/farmacologia , Inosina/uso terapêutico , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Doenças Neuroinflamatórias , Ratos , Ratos Wistar , Receptores Purinérgicos/metabolismo , EstreptozocinaRESUMO
Atherosclerosis is a multifactorial chronic disease, initiated by an endothelial dysfunction. Adenosine and its analogs can change a variety of inflammatory diseases and has shown important effects at different disease models. Inosine is a stable analogous of adenosine, but its effects in inflammatory diseases, like atherosclerosis, have not yet been studied. The aim of this study was to evaluate the pharmacological properties of inosine, administered sub chronically in a hypercholesterolemic model. Male Wistar rats were divided into four groups: control group (C) and control + inosine (C + INO) received standard chow, hypercholesterolemic diet group (HCD) and HCD + inosine (HCD + INO) were fed a hypercholesterolemic diet. At 31st experimentation day, the treatment with inosine was performed for C + INO and HCD + INO groups once daily in the last 15 days. We observed that the hypercholesterolemic diet promoted an increase in lipid levels and inflammatory cytokines production, while inosine treatment strongly decreased these effects. Additionally, HCD group presented a decrease in maximum relaxation acetylcholine induced and an increase in contractile response phenylephrine induced when compared to the control group, as well as it has presented an enhancement in collagen and ADP-induced platelet aggregation. On the other hand, inosine treatment promoted a decrease in contractile response to phenylephrine, evoked an improvement in endothelium-dependent vasorelaxant response and presented antiplatelet properties. Moreover, inosine activated eNOS and reduced p38 MAPK/NF-κB pathway in aortic tissues. Taken together, the present results indicate inosine as a potential drug for the treatment of cardiovascular disorders such as atherosclerosis.
Assuntos
Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Inosina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Aterosclerose/sangue , Aterosclerose/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Humanos , Inosina/farmacologia , Interleucina-6/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue , Vasodilatadores/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice. Pre-treatment of mice with NMDA (0.1 pmol/mouse, NMDAR agonist, i.c.v.) and D-serine (30 µg/mouse, NMDAR co-agonist, i.c.v.) prevented inosine (10 mg/kg, i.p.) anti-immobility effect in the TST. In addition, a synergistic antidepressant-like effect was observed when a sub-effective dose of inosine (0.1 mg/kg, i.p.) was combined with sub-effective doses of NMDAR antagonists MK-801 (0.001 mg/kg, p.o.) or ketamine (0.1 mg/kg, i.p.). Conversely, the antidepressant-like effect elicited by inosine was not altered by pre-treatment with AMPAR antagonist, DNQX (2.5 µg/mouse, i.c.v.). The mTORC1 inhibitor rapamycin (0.2 nmol/mouse, i.c.v.) prevented the inosine anti-immobility effect in the TST. Noteworthy, inosine treatment did not change the immunocontent of the synaptic proteins PSD95, GluA1 and synapsin I. Mice locomotor activity assessed by open-field test, was not altered by treatments. Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ácido Glutâmico/metabolismo , Inosina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Análise de Variância , Animais , Depressão/diagnóstico , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Relação Dose-Resposta a Droga , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Elevação dos Membros Posteriores/métodos , Masculino , Camundongos , Receptores de AMPA/metabolismoRESUMO
Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes were blocked by inosine treatment. Additionally, inosine consistently inhibited IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; A2AR: adenosine A2A receptor; IL-17: interleukin-17; IL-4: interleukin-4.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/prevenção & controle , Inosina/uso terapêutico , Receptor A2A de Adenosina/metabolismo , Animais , Ansiedade/complicações , Ansiedade/patologia , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Gliose/metabolismo , Gliose/patologia , Hiperalgesia/complicações , Hiperalgesia/patologia , Imunização , Imunomodulação , Inflamação/complicações , Inflamação/patologia , Inosina/farmacologia , Interleucina-17/biossíntese , Tecido Linfoide/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Bainha de Mielina/metabolismo , Fosforilação/efeitos dos fármacos , Medula Espinal/patologiaRESUMO
OBJECTIVE: To study the possible action of inosine on experimental ventricular tachyarrhythmias. MATERIAL AND METHODS: We used 92 mongrel dogs weighing 13 kg-17 kg, anesthetized with 30 mg/kg sodium pentobarbital applied intravenously. Myocardial lesions were induced by injecting 1 ml-1.5 ml of 70% phenol in the free wall of the left ventricle. In 36 dogs, the ventricular arrhythmia (VT) was induced 30 min later with aconitine crystals inserted into the periphery of the damaged area; in 16, VT was due only to myocardial damage and in the other 13 VT was spontaneously originated. Twenty-nine animals constituted the control group; no inosine was administered to them. The possible effects of inosine were studied in 63 animals. Leads II, aVR or aVL, right and Left unipolar intraventricular leads and that on the wall of the superior vena cava were recorded under control conditions, once the myocardial damage had been induced, during the ventricular tachycardia, and following the injection of inosine. Of the 63 inosine-treated animals; in 34, VT was due to aconitine; in 16, it was produced only by the myocardial damage and, in 13, VT was presented spontaneously. RESULTS: Sinus rhythm was not reestablished in the animals of the control group. Inosine reestablished the sinus rhythm in 26 of 34 dogs (76%) that received phenol and aconitine, in 13 of the 16 (81%) presenting only the myocardial damage, and in 6 of the 13 (46%) with spontaneous ventricular tachycardia. In some experiments, inosine induced supraventricular tachycardias, ventricular-atrial blocks, and ventricular pre-excitation phenomena. CONCLUSIONS: In this experimental series, inosine showed antiarrhythmic and arrhythmogenic effects, similar to those of adenosine from which it derives.
Assuntos
Inosina/uso terapêutico , Taquicardia Ventricular/prevenção & controle , Animais , CãesAssuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/terapia , Alopecia/diagnóstico , Antralina/uso terapêutico , Minoxidil/uso terapêutico , Corticosteroides/uso terapêutico , Alérgenos/uso terapêutico , Alopecia/tratamento farmacológico , Ciclosporina/uso terapêutico , Inosina/uso terapêutico , Líquen Plano/complicações , Lúpus Eritematoso Cutâneo/complicações , Guias de Prática Clínica como Assunto , Couro Cabeludo/efeitos dos fármacos , Tricotilomania/terapiaAssuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Alopecia/diagnóstico , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/terapia , Antralina/uso terapêutico , Minoxidil/uso terapêutico , Alérgenos/uso terapêutico , Inosina/uso terapêutico , Ciclosporina/uso terapêutico , Corticosteroides/uso terapêutico , Tricotilomania/terapia , Couro Cabeludo/efeitos dos fármacos , Líquen Plano/complicações , Lúpus Eritematoso Cutâneo/complicações , Guias de Prática Clínica como Assunto , Alopecia/tratamento farmacológicoRESUMO
O objetivo do presente estudo foi avaliar, em ratos, se o alopurinol é capaz de proteger o testículo contra os efeitos da isquemia com duraçäo de uma hora, seguida de reperfusäo. Dezoito ratos adultos, Wistar-EPM1, com peso variando entre 300 e 340g, foram divididos em três grupos: controle (G1), isquemia (G2) e isquemia com alopurinol (G3) com seis animais cada. Após anestesia com pentobarbital sódico intraperitoneal (30mg/Kg), o testículo esquerdo era exteriorizado e mantido imerso em soluçäo salina (0,9 por cento) à temperatura ambiente durante uma hora. Nos grupos G2 e G3 o pedículo era clampeado durante o experimento (1h). No grupo G3 cada animal recebeu 50 mg/Kg de alopurinol V.O. nos dois dias anteriores e duas horas antes da isquemia. Após 60 dias os animais foram anestesiados, sacrificados e os testículos removidos, pesados e preparados para exame histopatológico (HE). As lâminas foram analisadas de acordo com a classificaçäo de Cosentino. Observou-se diminuiçäo significante do peso do testículo esquerdo nos grupos G2 e G3 (p<0,05) e o escore histopatológico mostrou grau importante de sofrimento testicular esquerdo nos grupos G2 e G3 (p<0,05). Concluiu-se que o alopurinol näo foi capaz de proteger o testículo do rato contra os efeitos do fenômeno de isquemia/reperfusäo
Assuntos
Animais , Masculino , Ratos , Alopurinol/farmacologia , Alopurinol/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Inosina/uso terapêutico , Isquemia/tratamento farmacológico , Isquemia/patologia , Pentobarbital/uso terapêutico , Testículo/irrigação sanguínea , Testículo/patologia , Traumatismo por Reperfusão/patologia , Antimetabólitos/uso terapêutico , Catalase/uso terapêutico , Desferroxamina/uso terapêutico , Hiperóxia/metabolismo , Hipoxantina/farmacocinética , Nifedipino/uso terapêutico , Ratos Wistar , Superóxido Dismutase/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Vasodilatadores/uso terapêuticoRESUMO
Twenty patients with Acquired Immune Deficiency Syndrome (AIDS) received treatment with Inosine Pranobex and specific antibacterial and anti-parasitic therapy. Five died shortly after hospitalization, but a further fifteen who also received ACTH, survived, gained weight and improved clinically, biochemically and haematologically.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Hormônio Adrenocorticotrópico/uso terapêutico , Inosina Pranobex/uso terapêutico , Inosina/análogos & derivados , Inosina/uso terapêutico , Adolescente , Hormônio Adrenocorticotrópico/administração & dosagem , Adulto , Ensaios Clínicos como Assunto , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Inosina/administração & dosagem , Inosina Pranobex/administração & dosagem , Masculino , Pessoa de Meia-Idade , Trinidad e TobagoRESUMO
Analogues of purines, especially those of hypoxanthine and inosine, appear to hold considerable promise for the treatment of Chagas' disease.