RESUMO
Ischemic stroke is a major cause of morbidity and mortality worldwide and only few affected patients are able to receive treatment, especially in developing countries. Detailed pathophysiology of brain ischemia has been extensively studied in order to discover new treatments with a broad therapeutic window and that are accessible to patients worldwide. The nucleoside guanosine (Guo) has been shown to have neuroprotective effects in animal models of brain diseases, including ischemic stroke. In a rat model of focal permanent ischemia, systemic administration of Guo was effective only when administered immediately after stroke induction. In contrast, intranasal administration of Guo (In-Guo) was effective even when the first administration was 3 h after stroke induction. In order to validate the neuroprotective effect in this larger time window and to investigate In-Guo neuroprotection under global brain dysfunction induced by ischemia, we used the model of thermocoagulation of pial vessels in Wistar rats. In our study, we have found that In-Guo administered 3 h after stroke was capable of preventing ischemia-induced dysfunction, such as bilateral suppression and synchronicity of brain oscillations and ipsilateral cell death signaling, and increased permeability of the blood-brain barrier. In addition, In-Guo had a long-lasting effect on preventing ischemia-induced motor impairment. Our data reinforce In-Guo administration as a potential new treatment for brain ischemia with a more suitable therapeutic window.
Assuntos
Encéfalo/fisiopatologia , Guanosina/administração & dosagem , Guanosina/uso terapêutico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Administração Intranasal , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Veias Cerebrais/efeitos dos fármacos , Eletrocoagulação , Eletroencefalografia/efeitos dos fármacos , Lateralidade Funcional/efeitos dos fármacos , AVC Isquêmico/complicações , Masculino , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/prevenção & controle , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Ketamine has been reported to exert a prophylactic effect against stress-induced depressive-like behavior by modulating the guanosine-based purinergic system. However, the molecular pathways underlying its prophylactic effect and whether guanosine also elicits a similar effect remain to be determined. Here, we investigated the prophylactic effect of ketamine and guanosine against corticosterone (CORT - 20â¯mg/kg, p.o.)-induced depressive-like behavior in mice. Furthermore, we characterized if the prophylactic response may be associated with mTORC1-driven signaling in the hippocampus and prefrontal cortex. A single administration of ketamine (5â¯mg/kg, i.p.), but not guanosine (1 or 5â¯mg/kg, p.o.), given 1â¯week before the pharmacological stress prevented CORT-induced depressive-like behavior in the tail suspension test (TST) and splash test (SPT). Fluoxetine treatment for 3â¯weeks did not prevent CORT-induced behavioral effects. A single administration of subthreshold doses of ketamine (1â¯mg/kg, i.p.) plus guanosine (5â¯mg/kg, p.o.) partially prevented the CORT-induced depressive-like behavior in the SPT. Additionally, CORT reduced Akt (Ser473) and GSK-3ß (Ser9) phosphorylation and PSD-95, GluA1, and synapsin immunocontent in the hippocampus, but not in the prefrontal cortex. No alterations on mTORC1/p70S6K immunocontent were found in both regions in any experimental group. CORT-induced reductions on PSD-95, GluA1, and synapsin immunocontent were prevented only by ketamine treatment. Collectively, these findings suggest that ketamine, but not guanosine, exerts a prophylactic effect against depressive-like behavior, an effect associated with the stimulation of long-lasting pro-synaptogenic signaling in the hippocampus.
Assuntos
Corticosterona/toxicidade , Depressão/prevenção & controle , Guanosina/administração & dosagem , Ketamina/administração & dosagem , Profilaxia Pré-Exposição/métodos , Sinapses/fisiologia , Animais , Antidepressivos/administração & dosagem , Depressão/induzido quimicamente , Depressão/psicologia , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sinapses/efeitos dos fármacosRESUMO
Amyloid-ß oligomers (AßOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer's disease (AD). Considering presynaptic high energy demand and tight Ca2+ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AßOs was used to investigate the toxicity of AßOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AßOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AßOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca2+ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca2+ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Cálcio/metabolismo , Guanosina/farmacologia , Homeostase , Mitocôndrias/metabolismo , Neuroproteção/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/ultraestruturaRESUMO
Augmentative treatment is considered the best second-option when a first-choice drug has partial limitations, particularly by allowing antidepressant dose reduction. Considering that ketamine has significant knock-on effects, this study investigated the effects of a single coadministration with subthreshold doses of ketamine plus guanosine in a corticosterone (CORT)-induced animal model of depression and the role of anti-inflammatory and antioxidant pathways. CORT administration (20 mg/kg, p.o. for 21 days) increased the immobility time in the tail suspension test (TST) and the grooming latency in the splash test (SPT), as well as reduced the total time of grooming in the SPT. These behavioral alterations were accompanied by impaired hippocampal slices viability, elevated immunocontent of nuclear factor-kappa B (NF-κB) and indoleamine-2,3-dioxygenase 1 (IDO-1), and reduced immunocontent of glucocorticoids receptor (GR), glutamate transporter (GLT-1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in the hippocampus. CORT also decreased the thioredoxin reductase activity in the hippocampus, while reduced the glutathione reductase activity and non-protein thiols levels in both hippocampus and prefrontal cortex. In addition, elevated content of malondialdehyde and protein carbonyl was also observed in the hippocampus and prefrontal cortex of CORT-treated mice. Of note, a single administration of ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.) attenuated the depressive-like behavior and hippocampal slices impairments induced by CORT. The behavioral response obtained by the combined administration of these drugs was paralleled by the reestablishment of the CORT-induced molecular alterations on hippocampal GR, NF-κB, IDO-1, and GLT-1 immunocontent. Moreover, CORT-induced alterations on the antioxidant enzyme activity and oxidative stress markers were partially restored by ketamine plus guanosine treatment. Taken together, these findings suggest that guanosine might potentiate the effects of ketamine on inflammatory and oxidative markers that are elevated in depression.
Assuntos
Antidepressivos/administração & dosagem , Guanosina/administração & dosagem , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Ketamina/administração & dosagem , NF-kappa B/antagonistas & inibidores , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Corticosterona/toxicidade , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMO
The ketamine's potential for the treatment of refractory depression and anxiety has been considered one the most important discoveries in the last years, however, repeated use of ketamine is limited due to its side/adverse effects. Therefore, the search for effective augmentation strategies that may reduce ketamine doses is welcome. Therefore, this study sought to augment the effect of ketamine by guanosine in the novelty-suppressed feeding (NSF) test, a behavioral paradigm able to detect depression/anxiety-related behavior. Acute administration of guanosine (0.05â¯mg/kg, p.o.), similar to ketamine (1â¯mg/kg, i.p.), produced a rapid behavioral response in mice submitted to NSF test. Moreover, the coadministration of sub-effective doses of guanosine (0.01â¯mg/kg, p.o.) and ketamine (0.1â¯mg/kg, i.p.) was effective in mice submitted to NSF test. Subsequently, the intracellular mechanism underpinning the augmentation effect of ketamine by guanosine was investigated. Our results suggest that augmentation response of ketamine by guanosine in the NSF test probably involves the activation of mTOR signaling, since the treatment with rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor) completely abolished this effect. This augmentation strategy also increased mTOR phosphorylation (Ser2448) in the hippocampus, reinforcing the role of mTOR in this augmentation response. However, no changes in the p70S6K, PSD-95, GluA1, and synapsin immunocontents were found in the hippocampus of ketamine plus guanosine-treated mice. Overall, results provide evidence that guanosine is able to augment the effect of ketamine in the NSF test via mTOR activation, a finding that might have therapeutic implications for the management of depression/anxiety.
Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Guanosina/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Guanosina/administração & dosagem , Ketamina/administração & dosagem , CamundongosRESUMO
Guanosine (GUO) has neuroprotective effects in experimental models of brain diseases involving glutamatergic excitotoxicity in male animals; however, its effects in female animals are poorly understood. Thus, we investigated the influence of gender and GUO treatment in adult male and female Wistar rats submitted to focal permanent cerebral ischemia in the motor cortex brain. Female rats were subdivided into non-estrogenic and estrogenic phase groups by estrous cycle verification. Immediately after surgeries, the ischemic animals were treated with GUO or a saline solution. Open field and elevated plus maze tasks were conducted with ischemic and naïve animals. Cylinder task, immunohistochemistry and infarct volume analyses were conducted only with ischemic animals. Female GUO groups achieved a full recovery of the forelimb symmetry at 28-35 days after the insult, while male GUO groups only partially recovered at 42 days, in the final evaluation. The ischemic insult affected long-term memory habituation to novelty only in female groups. Anxiety-like behavior, astrocyte morphology and infarct volume were not affected. Regardless the estrous cycle, the ischemic injury affected differently female and male animals. Thus, this study points that GUO is a potential neuroprotective compound in experimental stroke and that more studies, considering the estrous cycle, with both genders are recommended in future investigation concerning brain diseases.
Assuntos
Isquemia Encefálica/prevenção & controle , Córtex Cerebral/efeitos dos fármacos , Guanosina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Caracteres Sexuais , Animais , Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologiaRESUMO
Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Experimental trauma involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Mitochondrial dysfunction and glutamatergic excitotoxicity are the hallmark mechanisms of damage. Accordingly, a successful pharmacological intervention requires a multi-faceted approach. Guanosine (GUO) is known for its neuromodulator effects in various models of brain pathology, specifically those that involve the glutamatergic system. The aim of the study was to investigate the GUO effects against mitochondrial damage in hippocampus and cortex of rats subjected to TBI, as well as the relationship of this effect with the glutamatergic system. Adult male Wistar rats were subjected to a unilateral moderate fluid percussion brain injury (FPI) and treated 15 min later with GUO (7.5 mg/kg) or vehicle (saline 0.9%). Analyses were performed in hippocampus and cortex 3 h post-trauma and revealed significant mitochondrial dysfunction, characterized by a disrupted membrane potential, unbalanced redox system, decreased mitochondrial viability, and complex I inhibition. Further, disruption of Ca2+ homeostasis and increased mitochondrial swelling was also noted. Our results showed that mitochondrial dysfunction contributed to decreased glutamate uptake and levels of glial glutamate transporters (glutamate transporter 1 and glutamate aspartate transporter), which leads to excitotoxicity. GUO treatment ameliorated mitochondrial damage and glutamatergic dyshomeostasis. Thus, GUO might provide a new efficacious strategy for the treatment acute physiological alterations secondary to TBI.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Lesões Encefálicas Traumáticas , Ácido Glutâmico/metabolismo , Guanosina/farmacologia , Doenças Mitocondriais , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Modelos Animais de Doenças , Guanosina/administração & dosagem , Masculino , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/fisiopatologia , Oxirredução/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Guanosine is a purine nucleoside that occurs naturally in the central nervous system, exerting trophic effects. Given its neuroprotective properties, the potential of guanosine as an antidepressant has been recently examined. Within this context, the present study sought to investigate the effects of chronic treatment with guanosine on the tail suspension test (TST), open field test and adult hippocampal neurogenesis. Swiss mice were administered guanosine for 21 days (5 mg/kg/day, p.o.) and subsequently submitted to the TST and open-field test. Following behavioural testing, animals were killed and the brains were processed for immunohistochemical analyses of hippocampal cell proliferation and neuronal differentiation. Animals treated with guanosine showed a reduction in immobility time in the TST without alterations in locomotor activity, confirming the antidepressant-like effect of this compound. Quantitative microscopic analysis did not reveal significant alterations in the numbers of Ki-67- and proliferating cell nuclear antigen (PCNA)-positive cells in the hippocampal dentate gyrus (DG) of guanosine-treated mice. However, guanosine treatment resulted in a significant increase in the number of immature neurons, as assessed by immunohistochemistry for the neurogenic differentiation protein. Interestingly, this effect was localized to the ventral hippocampal DG, a functionally distinct region of this structure known to regulate emotional and motivational behaviours. Taken together, our results suggest that the antidepressant-like effect of chronic guanosine treatment is associated with an increase in neuronal differentiation, reinforcing the notion that this nucleoside may be an endogenous mood modulator.
Assuntos
Guanosina/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Feminino , Guanosina/administração & dosagem , Hipocampo/citologia , Hipocampo/fisiologia , Locomoção , Camundongos , Neurônios/citologia , Neurônios/fisiologia , Fármacos Neuroprotetores/administração & dosagemRESUMO
In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [(3)H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO treatment prevented behavioral and brain impairment caused by ischemia in a therapeutically wide time window.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Guanosina/administração & dosagem , Guanosina/uso terapêutico , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Administração Intranasal , Animais , Comportamento Animal , Isquemia Encefálica/psicologia , Infarto Cerebral/patologia , Infarto Cerebral/prevenção & controle , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Guanosina/líquido cefalorraquidiano , Guanosina/farmacocinética , Masculino , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/líquido cefalorraquidiano , Fármacos Neuroprotetores/farmacocinética , Ratos , Ratos Wistar , Acidente Vascular Cerebral/psicologiaRESUMO
BACKGROUND AND PURPOSE: Stroke is a devastating disease. Both excitotoxicity and oxidative stress play important roles in ischemic brain injury, along with harmful impacts on ischemic cerebral tissue. As guanosine plays an important neuroprotective role in the central nervous system, the purpose of this study was to evaluate the neuroprotective effects of guanosine and putative cerebral events following the onset of permanent focal cerebral ischemia. METHODS: Permanent focal cerebral ischemia was induced in rats by thermocoagulation. Guanosine was administered immediately, 1 h, 3 h and 6 h after surgery. Behavioral performance was evaluated by cylinder testing for a period of 15 days after surgery. Brain oxidative stress parameters, including levels of ROS/RNS, lipid peroxidation, antioxidant non-enzymatic levels (GSH, vitamin C) and enzymatic parameters (SOD expression and activity and CAT activity), as well as glutamatergic parameters (EAAC1, GLAST and GLT1, glutamine synthetase) were analyzed. RESULTS: After 24 h, ischemic injury resulted in impaired function of the forelimb, caused brain infarct and increased lipid peroxidation. Treatment with guanosine restored these parameters. Oxidative stress markers were affected by ischemic insult, demonstrated by increased ROS/RNS levels, increased SOD expression with reduced SOD activity and decreased non-enzymatic (GSH and vitamin C) antioxidant defenses. Guanosine prevented increased ROS/RNS levels, decreased SOD activity, further increased SOD expression, increased CAT activity and restored vitamin C levels. Ischemia also affected glutamatergic parameters, illustrated by increased EAAC1 levels and decreased GLT1 levels; guanosine reversed the decreased GLT1 levels and did not affect the EAAC1 levels. CONCLUSION: The effects of brain ischemia were strongly attenuated by guanosine administration. The cellular mechanisms involved in redox and glutamatergic homeostasis, which were both affected by the ischemic insult, were also modulated by guanosine. These observations reveal that guanosine may represent a potential therapeutic agent in cerebral ischemia by preventing oxidative stress and excitotoxicity.
Assuntos
Lesões Encefálicas/prevenção & controle , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/fisiopatologia , Guanosina/farmacologia , Animais , Ácido Ascórbico/metabolismo , Western Blotting , Lesões Encefálicas/metabolismo , Isquemia Encefálica/etiologia , Catalase/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrocoagulação/efeitos adversos , Transportador 3 de Aminoácido Excitatório/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Membro Anterior/efeitos dos fármacos , Membro Anterior/fisiopatologia , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Glutamato-Amônia Ligase/metabolismo , Glutationa/metabolismo , Guanosina/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND AND PURPOSE: It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines on pain transmission. The aim of this study was to investigate the effects of intraperitoneal (i.p.) and oral (p.o.) administration of guanosine on mice pain models. Additionally, investigation into the mechanisms of action of guanosine, its potential toxicity and cerebrospinal fluid (CSF) purine levels were also assessed. EXPERIMENTAL APPROACH: Mice received an i.p. or p.o. administration of vehicle (0.1 mM NaOH) or guanosine (up to 240 mg x kg(-1)) and were evaluated in several pain models. KEY RESULTS: Guanosine produced dose-dependent antinociceptive effects in the hot-plate, glutamate, capsaicin, formalin and acetic acid models, but it was ineffective in the tail-flick test. Additionally, guanosine produced a significant inhibition of biting behaviour induced by i.t. injection of glutamate, AMPA, kainate and trans-ACPD, but not against NMDA, substance P or capsaicin. The antinociceptive effects of guanosine were prevented by selective and non-selective adenosine receptor antagonists. Systemic administration of guanosine (120 mg x kg(-1)) induced an approximately sevenfold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by intraplantar capsaicin. CONCLUSIONS AND IMPLICATIONS: This study provides new evidence on the mechanism of action of the antinociceptive effects after systemic administration of guanosine. These effects seem to be related to the modulation of adenosine A(1) and A(2A) receptors and non-NMDA glutamate receptors.
Assuntos
Analgésicos/uso terapêutico , Guanosina/uso terapêutico , Dor/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/líquido cefalorraquidiano , Analgésicos/farmacologia , Analgésicos/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Guanosina/administração & dosagem , Guanosina/líquido cefalorraquidiano , Guanosina/farmacologia , Guanosina/toxicidade , Injeções Intraperitoneais , Dose Letal Mediana , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Dor/líquido cefalorraquidiano , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that intracerebroventricular (i.c.v.) administered guanine-based purines are antinociceptive against chemical and thermal pain models in mice. The present study was designed to further investigate the antinociceptive effects of guanosine in mice. Animals received an intrathecal (i.t.) injection of vehicle (0.1 mN NaOH) or guanosine (10 to 400 nmol). Measurements of cerebrospinal fluid (CSF) purine levels and spinal cord glutamate uptake were performed. Guanosine produced dose-dependent antinociceptive effects against tail-flick, hot-plate, intraplantar (i.pl.) capsaicin, and i.pl. glutamate tests. Additionally, i.t. guanosine produced significant inhibition of the biting behavior induced by i.t. injection of glutamate (175 nmol/site), AMPA (135 pmol/site), kainate (110 pmol/site), trans-ACPD (50 nmol/site), and substance P (135 ng/site), with mean ID(50) values of 140 (103-190), 136 (100-185), 162 (133-196), 266 (153-461) and 28 (3-292) nmol, respectively. However, guanosine failed to affect the nociception induced by NMDA (450 pmol/site) and capsaicin (30 ng/site). Intrathecal administration of guanosine (200 nmol) induced an approximately 120-fold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by i.pl. capsaicin. This study provides new evidence on the mechanism of action of guanosine presenting antinociceptive effects at spinal sites. This effect seems to be at least partially associated with modulation of glutamatergic pathways by guanosine.
Assuntos
Analgésicos/farmacologia , Guanosina/farmacologia , Coluna Vertebral/efeitos dos fármacos , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Guanosina/uso terapêutico , Injeções Espinhais , Masculino , Camundongos , Neuroquímica , Dor/líquido cefalorraquidiano , Dor/tratamento farmacológico , Dor/metabolismo , Purinas/líquido cefalorraquidiano , Coluna Vertebral/metabolismoRESUMO
Perinatal cerebral hypoxia-ischemia (HI) is an important cause of mortality and neurological disabilities such as cerebral palsy, epilepsy, and mental retardation. The potential for neuroprotection in HI can be achieved mainly during the recovery period. In previous work, we demonstrated that guanosine (Guo) prevented the decrease of glutamate uptake by hippocampal slices of neonatal rats exposed to a hypoxic-ischemic (HI) insult in vivo when administrated before and after insult. In the present study, we compared the effect of Guo administration only after HI using various protocols. When compared with the control, a decrease of [(3)H] glutamate uptake was avoided only when three doses of Guo were administered immediately, 24 h and 48 h after insult, or at 3 h, 24 h, and 48 h after injury or at 6 h, 24 h, and 48 h after HI. These findings indicate that early Guo administration (until 6 h) after HI, in three doses may enhance glutamate uptake into brain slices after hypoxia/ischemia, probably resulting in decreased excitotoxicity.
Assuntos
Esquema de Medicação , Guanosina , Hipóxia-Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Guanosina/administração & dosagem , Guanosina/uso terapêutico , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Resultado do TratamentoRESUMO
It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines (GBPs) on pain transmission. The aim of this study was to investigate the effects of intracerebroventricular (i.c.v.) guanosine and GMP on mice pain models. Mice received an i.c.v. injection of vehicle (saline or 10 muM NaOH), guanosine (5 to 400 nmol), or GMP (240 to 960 nmol). Additional groups were also pre-treated with i.c.v. injection of the A(1)/A(2A) antagonist caffeine (15 nmol), the non-selective opioid antagonist naloxone (12.5 nmol), or the 5'-nucleotidase inhibitor AOPCP (1 nmol). Measurements of CSF purine levels and cortical glutamate uptake were performed after treatments. Guanosine and GMP produced dose-dependent antinociceptive effects. Neither caffeine nor naloxone affected guanosine antinociception. Pre-treatment with AOPCP completely prevented GMP antinociception, indicating that conversion of GMP to guanosine is required for its antinociceptive effects. Intracerebroventricular administration of guanosine and GMP induced, respectively, a 180- and 1800-fold increase on CSF guanosine levels. Guanosine was able to prevent the decrease on cortical glutamate uptake induced by intraplantar capsaicin. This study provides new evidence on the mechanism of action of GBPs, with guanosine and GMP presenting antinociceptive effects in mice. This effect seems to be independent of adenosine and opioid receptors; it is, however, at least partially associated with modulation of the glutamatergic system by guanosine.
Assuntos
Analgésicos , Guanosina Monofosfato/farmacologia , Guanosina/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Capsaicina , Cromatografia Líquida de Alta Pressão , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Guanosina/líquido cefalorraquidiano , Guanosina Monofosfato/administração & dosagem , Guanosina Monofosfato/líquido cefalorraquidiano , Temperatura Alta , Injeções Intraventriculares , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacosRESUMO
Brain injury secondary to hypoxic-ischemic disease is the predominant form of damage encountered in the perinatal period. The impact of neonatal hypoxia-ischemia (HI) in 7-day-old pups on the high-affinity [3H] glutamate uptake into hippocampal slices at different times after insult was examined. Immediately following, and 1 day after the insult there was no effect. But at 3 to 5 days after the HI insult, glutamate uptake into the hippocampus was markedly reduced; however, after 30 or 60 days the glutamate uptake into hippocampal slices returned to control levels. Also, this study demonstrated the effect of the nucleoside guanosine (Guo) on the [3H] glutamate uptake in neonatal HI injury, maintaining the [3H] glutamate uptake at control levels when injected before and after insult HI. We conclude that neonatal HI influences glutamate uptake a few days following insult, and that guanosine prevents this action.
Assuntos
Infarto Encefálico/prevenção & controle , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Infarto Encefálico/etiologia , Hipocampo/metabolismo , Hipóxia-Isquemia Encefálica/complicações , Técnicas In Vitro , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Oral and intraperitoneal administration of the nucleoside guanosine have been shown to prevent quinolinic acid- (QA) and alpha-dendrotoxin-induced seizures, impair memory, and impair anxiety in rats and mice. We investigated the effect of 2-weeks ad lib orally administered guanosine (0.5 mg/ml) on seizures induced by QA, inhibitory avoidance memory, and locomotor performance in rats. We also studied the mechanism of action of guanosine through the measurement of its concentration in the cerebrospinal fluid (CSF) and its effect on glutamate uptake in cortical slices of rats. QA produced seizures in 85% of rats, an effect partially prevented by guanosine (53% of seizures; P = 0.0208). Guanosine also impaired retention on the inhibitory avoidance task (P = 0.0278) and decreased locomotor activity on the open field test (P = 0.0101). The CSF guanosine concentration increased twofold in the treated group compared to that in the vehicle group (P = 0.0178). Additionally, QA promoted a 30% decrease in glutamate uptake as compared to that with intracerebroventricular saline administration, an effect prevented by guanosine in animals protected against QA-induced seizures. Altogether, these findings suggest a potential role of guanosine for treating diseases involving glutamatergic excitotoxicity such as epilepsy. These effects seem to be related to modulation of glutamate uptake.
Assuntos
Comportamento Animal/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Convulsões/induzido quimicamente , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Esquema de Medicação , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Guanosina/toxicidade , Inibição Psicológica , Masculino , Ácido Quinolínico/toxicidade , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Convulsões/líquido cefalorraquidianoRESUMO
Extracellular guanine-based purines, mainly the nucleoside guanosine, have recently been shown to exert neuroprotective effects, which seem to be related to antagonism of the glutamatergic system. In this study, we investigated the effects of acute oral administration of guanosine on inhibitory avoidance task in rats and mice. We also studied its effects on locomotor activity, anxiety-related behaviors and mechanisms of action involving the purinergic system. Guanosine (2.0 and 7.5mg/kg, per os), administered 75min pretraining, dose-dependently impaired retention of the inhibitory avoidance task in rats and mice, an effect not prevented by the adenosine receptor antagonist caffeine. Guanosine presented no effects on locomotor activity and anxiety-related behaviors. This amnesic effect of guanosine may be compatible with inhibition of glutamatergic system and seems to be not mediated by adenosine.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Guanosina/efeitos adversos , Inibição Psicológica , Aprendizagem em Labirinto/efeitos dos fármacos , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Guanosina/administração & dosagem , Masculino , Camundongos , Ratos , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
BACKGROUND AND METHODS: In this study, we investigated the effect of 8-bromoguanosine (8Brguo), an immunostimulatory compound, in a murine model of experimental cutaneous leishmaniasis. RESULTS: The results indicated that treatment by intraperitoneal administration of 8Brguo (150 mg/kg once daily for 1 week and thereafter once weekly for 1 month) diluted in Tween-80 produces an effect similar to that of treatment with the classical antimonial drug, Glucantime, in Leishmania amazonensis-infected CBA/J mice. While complete cure did not occur, animals treated with the nucleoside had small lesions in the infected footpad and delayed surface ulceration. Studies involving examination of serum glutamic pyruvic transaminase activity, concentration of urea, blood pathology and histology of the spleen, kidney and liver showed no apparent toxicity of the nucleoside in treated mice. CONCLUSION: The protective in vivo effect during murine leishmaniasis as well as the lack of apparent toxicity of 8Brguo as attested by blood/serum pathology and histology from treated mice encourage further studies of C8-substituted guanine ribonucleosides, such as 8Brguo, as new leishmanial drugs and as modifiers of the immunological response to combat infections with intracellular pathogens.
Assuntos
Guanosina/análogos & derivados , Guanosina/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Úlcera Cutânea/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Alanina Transaminase/sangue , Animais , Feminino , Guanosina/administração & dosagem , Testes Hematológicos , Injeções Intraperitoneais , Leishmaniose Cutânea/sangue , Meglumina/administração & dosagem , Meglumina/uso terapêutico , Antimoniato de Meglumina , Camundongos , Camundongos Endogâmicos CBA , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/uso terapêutico , Úlcera Cutânea/sangue , Úlcera Cutânea/parasitologia , Tripanossomicidas/administração & dosagem , Ureia/sangueRESUMO
Acute administration of intraperitoneal and oral guanosine has been shown to prevent quinolinic acid and alpha-dendrotoxin-induced seizures in rats and mice. In this study, we investigated the effects of 2 weeks ad libitum consumption of guanosine (0.5 mg/ml) added to mice water supply on seizures and lethality induced by the alpha-dendrotoxin, hole-board behavior, inhibitory avoidance task, locomotor activity, motor coordination, rectal temperature, body weight, and water and food consumption. Guanosine prevented seizures in 40% and death in 50% on mice treated with i.c.v. alpha-dendrotoxin; it also impaired inhibitory avoidance memory and increased head-dipping behavior and locomotor activity on the hole-board test. Guanosine consumption did not alter any of the other parameters evaluated. The anticonvulsant, amnesic, and anxyolytic-like effects may be associated with the ability of guanosine in modulating the glutamatergic excitatory system. Adding to previously reported data, these findings suggest a potential role for chronic guanosine in the management of diseases associated with glutamatergic excitotoxicity, including epilepsy and anxiety.