RESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative illness responsible for cognitive impairment and dementia. Accumulation of amyloid-beta (Aß) peptides in neurons and synapses causes cell metabolism to unbalance, and the production of reactive oxygen species (ROS), leading to neuronal death and cognitive damage. Guanosine is an endogenous nucleoside recognized as a neuroprotective agent since it prevents glutamate-induced neurotoxicity by a mechanism not yet completely elucidated. In this study, we evaluated behavioral and biochemical effects in the hippocampus caused by the intracerebroventricular (i.c.v.) infusion of Aß1-42 peptide (400 pmol/site) in mice, and the neuroprotective effect of guanosine (8 mg/kg, i.p.). An initial evaluation on the eighth day after Aß1-42 infusion showed no changes in the tail suspension test, although ex vivo analyses in hippocampal slices showed increased ROS production. In the second protocol, on the tenth day following Aß1-42 infusion, no effect was observed in the sucrose splash test, but a reduction in the recognition index in the object location test showed impaired spatial memory. Analysis of hippocampal slices showed no ROS production and mitochondrial membrane potential alteration, but a tendency to increase glutamate release and a significant lactate release, pointing to a metabolic alteration. Those effects were accompanied by decreased cell viability and increased membrane damage. Guanosine treatment prevented behavioral and biochemical alterations evoked by Aß1-42, suggesting a potential role against behavioral and biochemical damage evoked by Aß in the hippocampus.
RESUMO
Degeneration of the locus coeruleus (LC), the main source of cerebral noradrenaline (NA), has been reported in diverse neurodegenerative diseases, including Parkinson's diseases (PD). There is increasing evidence indicating the role of NA deficiency in the prefrontal cortex (PFC) and the development of early cognitive impairments in PD. Here, we evaluated whether a selective noradrenergic lesion of LC caused by 6-hydroxydopamine (6-OHDA) may induce memory deficits and neurochemical alterations in the PFC. Adult male Wistar rats received stereotaxic bilateral injections of 6-OHDA (5 µg/2 µl) into the LC, and two stainless-steel guide cannulas were implanted in the PFC. The SHAM group received just vehicle. To induce a selective noradrenergic lesion, animals received nomifensine (10 mg/kg), a dopamine transporter blocker, one hour before surgery. 6-OHDA-lesioned rats displayed impairments of the short- and long-term object recognition memory associated to reduced content of tyrosine hydroxylase in the LC. Neurochemical analysis revealed an altered mitochondrial membrane potential in LC. Regarding the PFC, an increased ROS production, cell membrane damage, and mitochondrial membrane potential disruption were observed. Remarkably, bilateral NA (1 µg/0.2 µl) infusion into the PFC restored the recognition memory deficits in LC-lesioned rats. These findings indicate that a selective noradrenergic LC lesion induced by 6-OHDA deregulates a noradrenergic network in the PFC, which could be involved in the early memory impairments observed in nondemented PD patients.
Assuntos
Locus Cerúleo/patologia , Transtornos da Memória/patologia , Oxidopamina/efeitos adversos , Córtex Pré-Frontal/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos WistarRESUMO
Stroke is a major cause of disability and death worldwide. Oxygen and glucose deprivation (OGD) in brain tissue preparations can reproduce several pathological features induced by stroke providing a valuable ex vivo protocol for studying the mechanism of action of neuroprotective agents. Guanosine, an endogenous guanine nucleoside, promotes neuroprotection in vivo and in vitro models of neurotoxicity. We previously showed that guanosine protective effect was mimicked by inhibition of nitric oxide synthases (NOS) activity. This study was designed to investigate the involvement of nitric oxide (NO) in the mechanisms related to the protective role of guanosine in rat hippocampal slices subjected to OGD followed by reoxygenation (OGD/R). Guanosine (100 µM) and the pan-NOS inhibitor, L-NAME (1 mM) afforded protection to hippocampal slices subjected to OGD/R. The presence of NO donors, DETA-NO (800 µM) or SNP (5 µM) increased reactive species production, and abolished the protective effect of guanosine or L-NAME against OGD/R. Guanosine or L-NAME treatment prevented the impaired ATP production, lactate release, and glutamate uptake following OGD/R. The presence of a NO donor also abolished the beneficial effects of guanosine or L-NAME on bioenergetics and glutamate uptake. These results showed, for the first time, that guanosine may regulate cellular bioenergetics in hippocampal slices subjected to OGD/R injury by a mechanism that involves the modulation of NO levels.
Assuntos
Trifosfato de Adenosina/metabolismo , Ácido Glutâmico/metabolismo , Guanosina/farmacologia , Ácido Láctico/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Animais , Hipóxia Celular/fisiologia , Glucose/deficiência , Hipocampo/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Oxigênio/metabolismo , Ratos Wistar , Triazenos/farmacologiaRESUMO
The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson's disease (PD). Beyond the nigrostriatal pathway, dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC) and hippocampus, which have been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Herein, using behavioral and biochemical approaches, we investigated the protective effects of guanosine (GUO) (7.5â¯mg/kg, i.p.) against emotional impairments and cellular events in cortical, striatal and hippocampal slices of rats submitted to a bilateral infusion of 6-OHDA (10⯵g/hemisphere) into the DLS. 6-OHDA-lesioned rats displayed anhedonic- and depressive-like behaviors addressed in the splash and forced swimming tests (at 8 and 21 days after lesion, respectively). In addition, no alterations in motor performance in the open field test and social interaction were observed. Biochemical analyses were performed 22 days after 6-OHDA lesions. 6-OHDA lesion induced hippocampal mitochondrial membrane potential disruption. However, intra-striatal 6-OHDA administration did not alter the ROS levels measured in cortical, striatal and hippocampal slices. GUO treatment attenuated anhedonic- and depressive-like behaviors in 6-OHDA-lesioned rats and protected hippocampal slices against the mitochondrial membrane potential disruption. These results indicate antidepressant-like effects of GUO in a rat model of PD, indicating the potential of GUO for the treatment of depression associated with PD.
Assuntos
Depressão/metabolismo , Depressão/prevenção & controle , Guanosina/farmacologia , Anedonia/fisiologia , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Dopamina/metabolismo , Guanosina/metabolismo , Hipocampo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Neostriado/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/patologia , Ratos , Ratos WistarRESUMO
Intracerebroventricular (icv) amyloid-beta (Aß)1-40 infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aß1-40 infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aß1-40-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aß1-40 (400 pmol/site, icv) infusion. Aß1-40-induced hippocampal cell damage was reversed by atorvastatin treatment. Aß1-40 infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aß1-40-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Atorvastatina/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Depressão/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Atorvastatina/farmacologia , Depressão/metabolismo , Glutamato-Amônia Ligase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologiaRESUMO
Atorvastatin has been shown to exert a neuroprotective action by counteracting glutamatergic toxicity. Recently, we have shown atorvastatin also exerts an antidepressant-like effect that depends on both glutamatergic and serotonergic systems modulation. Excitotoxicity is involved in several brain disorders including depression; thus, it is suggested that antidepressants may target glutamatergic system as a final common pathway. In this study, a comparison of the mechanisms involved in the putative neuroprotective effect of a repetitive atorvastatin or fluoxetine treatment against glutamate toxicity in hippocampal slices was performed. Adult Swiss mice were treated with atorvastatin (10 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.), once a day during seven consecutive days. On the eighth day, animals were killed and hippocampal slices were obtained and subjected to an in vitro protocol of glutamate toxicity. An acute treatment of atorvastatin or fluoxetine was not neuroprotective; however, the repeated atorvastatin or fluoxetine treatment prevented the decrease in cellular viability induced by glutamate in hippocampal slices. The loss of cellular viability induced by glutamate was accompanied by increased D-aspartate release, increased reactive oxygen species (ROS) and nitric oxide (NO) production, and impaired mitochondrial membrane potential. Atorvastatin or fluoxetine repeated treatment also presented an antidepressant-like effect in the tail suspension test. Atorvastatin or fluoxetine treatment was effective in protecting mice hippocampal slices from glutamate toxicity by preventing the oxidative stress and mitochondrial dysfunction.
Assuntos
Atorvastatina/farmacologia , Fluoxetina/farmacologia , Ácido Glutâmico/toxicidade , Hipocampo/patologia , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Atorvastatin is a cholesterol-lowering statin that has been shown to exert several pleiotropic effects in the nervous system as a neuroprotective and antidepressant-like agent. Antidepressant-like effect of atorvastatin in mice is mediated by glutamatergic and serotoninergic receptors, although the precise intracellular signaling pathways involved are unknown. PI3K/Akt/GSK-3ß/mTOR signaling pathway has been associated to neurobiology of depression and seems to be modulated by some pharmacological antidepressant strategies. The present study investigated the participation of the PI3K/Akt/GSK-3ß/mTOR signaling pathway in the antidepressant-like effect of an acute atorvastatin treatment in mice. Atorvastatin sub-effective (0.01 mg/kg) or effective (0.1 mg/kg) doses in the tail suspension test (TST) was administered orally alone or in combination with PI3K, GSK-3ß or mTOR inhibitors. The administration of PI3K inhibitor, LY294002 (10 nmol/site, i.c.v) completely prevented the antidepressant-like effect of atorvastatin (0.1 mg/kg, p.o.). The participation of GSK-3ß in the antidepressant-like effect of atorvastatin was demonstrated by co-administration of a sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) with AR-A014418 (0.01 µg/site, i.c.v., a selective GSK-3ß inhibitor) or with lithium chloride (10 mg/kg, p.o., a non-selective GSK-3ß inhibitor). The mTOR inhibitor, rapamycin (0.2 nmol/site, i.c.v.) was also able to prevent atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. These behavioral findings were supported by neurochemical observations, as atorvastatin treatment increased the immunocontent of the phosphorylated isoforms of Akt, GSK-3ß and mTOR in the hippocampus of mice. Taken together, our results suggest an involvement of the PI3K/Akt/GSK-3ß/mTOR signaling pathway in the antidepressant-like effect of atorvastatin in mice.
Assuntos
Antidepressivos/uso terapêutico , Atorvastatina/uso terapêutico , Depressão/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Análise de Variância , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Elevação dos Membros Posteriores/métodos , Imunossupressores/farmacologia , Masculino , Camundongos , Proteína Oncogênica v-akt/metabolismo , Sirolimo/farmacologia , Fatores de TempoRESUMO
Environmental enrichment (EE) is a non-pharmacological manipulation that promotes diverse forms of benefits in the central nervous system of captive animals. It is thought that EE influences animal behavior in a specie-(strain)-specific manner. Since rodents in general present different behaviors during distinct periods of the day, in this study we aimed to investigate the influence of time-of-day on behavioral repertoire of Swiss mice that reared in EE. Forty male Swiss mice (21days old) were housed in standard (SC) or enriched conditions (EC) for 60days. Behavioral assessments were conducted during the light phase (in presence of light) or dark phase (in absence of light) in the following tasks: open field, object recognition and elevated plus maze. First, we observed that the locomotor and exploratory activities are distinct between SC and EC groups only during the light phase. Second, we observed that "self-protective behaviors" were increased in EC group only when mice were tested during the light phase. However, "less defensive behaviors" were not affected by both housing conditions and time-of-day. Third, we showed that the performance of EE animals in object recognition task was improved in both light and dark conditions. Our findings highlight that EE-induced alterations in exploratory and emotional behaviors are just evident during light conditions. However, EE-induced cognitive benefits are remarkable even during dark conditions, when exploratory and emotional behaviors were similar between groups.
Assuntos
Comportamento Animal/fisiologia , Meio Ambiente , Comportamento Exploratório/fisiologia , Aprendizagem em Labirinto/fisiologia , Atividade Motora/fisiologia , Animais , Abrigo para Animais , Masculino , CamundongosRESUMO
Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice. Data demonstrate that the serotonin (5-HT) depleting agent p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p.) completely abolished atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. Besides atorvastatin, fluoxetine (10 mg/kg, p.o.), a serotonin selective reuptake inhibitor (SSRI) was able to exert an antidepressant-like effect, but any of them changed 5-HT content in the hippocampus or frontal cortex. The 5H-T1A (WAY100635, 0.1 mg/kg, s.c) or the 5-HT2A/2C (ketanserin, 5 mg/kg, s.c.) receptor antagonists prevented atorvastatin antidepressant-like effect. In addition, a combinatory antidepressant-like effect was observed when mice received the co-administration of sub-effective doses of atorvastatin (0.01 mg/kg, p.o.) and the SSRI fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.). Taken together, these results indicate that the antidepressant-like effect of atorvastatin depends on the serotonergic system modulation.