RESUMO
Senescence-accelerated mouse prone 8 (SAMP8) is a model of aging characterized by the early onset of learning and memory impairment and various pathological features of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, and NMDA receptor antagonist-treated mice. Here, we present evidence that this natural compound improves age-related cognitive impairment and reduces oxidative stress and tau phosphorylation in SAMP8 mice. Treatment with nobiletin (10 or 50mg/kg) reversed the impairment of recognition memory and context-dependent fear memory in SAMP8 mice. Treatment with nobiletin also restored the decrease in the GSH/GSSG ratio in the brain of SAMP8 mice. In addition, increases in glutathione peroxidase and manganese-superoxide dismutase activities, as well as a decrease in protein carbonyl level, were observed in the brain of nobiletin-treated SAMP8 mice. Furthermore, nobiletin reduced tau phosphorylation in the hippocampus of SAMP8 mice. Together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the learning and memory deficits, oxidative stress, and hyperphosphorylation of tau in aging as well as age-related neurodegenerative diseases such as AD.
Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Flavonas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Proteínas tau/metabolismo , Envelhecimento/genética , Envelhecimento/fisiologia , Análise de Variância , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Estudos de Casos e Controles , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Flavonas/química , Flavonas/farmacologia , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
We have recently found that combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and mice and that estrogen replacement and chronic treatment with Ginkgo biloba extract EGb 761 suppress the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of placental extract on the memory impairment and neuromorphological change in OVX/stress-subjected mice. Female Slc:ICR strain mice were randomly divided into four groups: vehicle-treated OVX, porcine placental extract (120 and 2160 mg/kg)-treated OVX, and sham-operated control groups. Two weeks after surgical operation, OVX mice underwent restraint stress for 21 days (6 h/day), and all animals were then subjected to a contextual fear conditioning test followed by morphological examination by Nissl staining. Placental extract was orally administered once daily until the behavioral analysis was carried out. Chronic treatment with both doses of placental extract improved the OVX/stress-induced fear memory impairment and Nissl-positive cell loss of the hippocampal CA3 region, although it did not affect the loss of bone mineral density and increase in body weight after OVX. These results have important implications for the neuroprotective and cognition-enhancing effects of placental extract in postmenopausal women.
Assuntos
Medo , Ginkgo biloba/química , Hipocampo/efeitos dos fármacos , Imobilização , Transtornos da Memória/patologia , Neurônios/patologia , Ovariectomia , Placenta/química , Extratos Vegetais/farmacologia , Estresse Fisiológico , Animais , Densidade Óssea/efeitos dos fármacos , Feminino , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos ICR , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Útero/efeitos dos fármacosRESUMO
INTRODUCTION: We previously demonstrated that synovial sublining macrophages express folate receptor beta (FRß). The aim of this study was to evaluate the efficacy of intra-articular administration of a recombinant immunotoxin to FRß for treating rat antigen-induced arthritis. METHODS: A monoclonal antibody (mAb) to rat FRß was produced by immunizing mice with B300-19 cells (murine pre-B cells) transfected with the rat FRß gene. Recombinant immunotoxin was prepared by conjugating the Fv portion of the anti-rat FRß mAb heavy chain with a truncated Pseudomonas exotoxin A and the Fv portion of the anti-rat FRß mAb light chain. Antigen-induced arthritis was induced through intra-articular injection of methylated bovine serum albumin (mBSA) after two subcutaneous injections of mBSA and complete Freund's adjuvant. Immunotoxin was intra-articularly injected into the arthritis joint every other day for seven days after arthritis onset. Joint swelling was measured and histological scores of inflammation, synovial thickness, cartilage, and bone destruction were determined. Immunohistochemistry was performed to detect osteoclast and osteoclast precursor FRß-expressing macrophages and cathepsin K-positive cells on day 21. RESULTS: Intra-articular administration of the immunotoxin attenuated joint swelling (61% suppression; P < 0.01 compared to the control on day 21) and improved histological findings, particularly cartilage and bone destruction (scores of rats treated with control versus the immunotoxin: 2.2 versus 0.5; P < 0.01), by reducing the number of FRß-expressing macrophages and cathepsin K-positive cells. CONCLUSIONS: Intra-articular administration of an immunotoxin to FRß is effective for improving rat antigen-induced arthritis.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Receptor 2 de Folato/antagonistas & inibidores , Receptor 2 de Folato/imunologia , Imunotoxinas/administração & dosagem , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Imunotoxinas/imunologia , Injeções Intra-Articulares , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Ratos , Ratos Endogâmicos LewRESUMO
N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.
Assuntos
Proliferação de Células/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ácido Glutâmico/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/patologia , Fenciclidina/efeitos adversos , Córtex Pré-Frontal/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Estimulação Acústica , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Sintomas Comportamentais/induzido quimicamente , Peso Corporal/efeitos dos fármacos , Bromodesoxiuridina/metabolismo , Embrião de Mamíferos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microdissecção , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Natação/psicologiaRESUMO
Cognitive deficits are a core feature of patients with methamphetamine (METH) abuse. It has been reported that repeated METH treatment impairs long-term recognition memory in the novel object recognition test (NORT) in mice. Recent studies indicate that silibinin, a flavonoid derived from the herb milk thistle, has potent neuroprotective effects in cell cultures and several animal models of neurological diseases. However, its effect on the cognitive deficit induced by METH remains unclear. In the present study, we attempt to clarify the effect of silibinin on impairments of recognition memory caused by METH in mice. Mice were co-administered silibinin with METH for 7 days and then cognitive function was assessed by NORT after 7-day withdrawal. Tissue levels of dopamine and serotonin as well as their metabolites in the prefrontal cortex and hippocampus were measured 1 day after NORT. Silibinin dose-dependently ameliorated the impairment of recognition memory caused by METH treatment in mice. Silibinin significantly attenuated the decreases in the dopamine content of the prefrontal cortex and serotonin content of the hippocampus caused by METH treatment. We also found a correlation between the recognition values and dopamine and serotonin contents of the prefrontal cortex and hippocampus. The effect of silibinin on cognitive impairment may be associated with an amelioration of decreases in dopamine and serotonin levels in the prefrontal cortex and hippocampus, respectively. These results suggest that silibinin may be useful as a pharmacological tool to investigate the mechanisms of METH-induced cognitive impairments.
Assuntos
Encéfalo/efeitos dos fármacos , Dopaminérgicos/toxicidade , Transtornos da Memória/tratamento farmacológico , Metanfetamina/toxicidade , Nootrópicos/farmacologia , Animais , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Dopamina/metabolismo , Dopaminérgicos/administração & dosagem , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR , Nootrópicos/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Serotonina/metabolismo , Silibina , Silimarina/administração & dosagem , Silimarina/farmacologiaRESUMO
BACKGROUND: Prepulse inhibition (PPI) of the startle response is a measure of the inhibitory function and time-linked information processing by which a weak sensory stimulus (the prepulse) inhibits the startle response caused by a sudden intense stimulus. We attempted to clarify the neuronal circuits underlying the control of PPI of the startle reflex in mice. METHODS: c-Fos immunohistochemistry was used to detect neurons activated by startle pulse and/or prepulse trials. Behavioural pharmacology and tracing studies were also conducted. RESULTS: The lateral globus pallidus (LGP) was activated by prepulses. Activation of the caudal pontine reticular nucleus (PnC) evoked by the startle pulses was inhibited under PPI conditions. Double-immunostaining revealed that c-Fos-positive cells in the LGP following prepulse trials were GABAergic neurons. Bilateral microinjections of lidocaine into the LGP resulted in an impairment of PPI. Fluoro-gold infusion into the PnC and the pedunculopontine tegmental nucleus (PPTg) retrogradely labeled neurons in the PPTg and LGP, respectively. Microinjections of phaclofen into the PPTg significantly impaired PPI. CONCLUSIONS: These results suggest that GABAergic neurons in the LGP which project to the PPTg play a crucial role through the activation of GABAB receptors in the regulation of PPI of the startle reflex in mice.
Assuntos
Comportamento Animal/fisiologia , Habituação Psicofisiológica/fisiologia , Neurônios/fisiologia , Núcleo Tegmental Pedunculopontino/fisiologia , Reflexo de Sobressalto/fisiologia , Ácido gama-Aminobutírico/fisiologia , Estimulação Acústica , Animais , Comportamento Animal/efeitos dos fármacos , Genes fos/fisiologia , Globo Pálido/fisiologia , Imuno-Histoquímica , Lidocaína/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Vias Neurais/fisiologia , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Receptores de GABA-B/efeitos dos fármacos , Receptores de GABA-B/fisiologia , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
In the present study, we investigated how the neurosteroid, dehydroepiandrosterone sulfate (DHEAS) affects the development of morphine dependence and tolerance in mice. Mice administered morphine (10 mg/kg) twice a day for 5 days developed tolerance to the analgesic effect and dependence as shown by a severe withdrawal syndrome induced by naloxone. Co-administration of DHEAS (10 mg/kg) with morphine significantly inhibited the development, but not the expression, of tolerance to morphine-induced analgesia and the naloxone-precipitated withdrawal. The expression of c-fos mRNA was observed in the frontal cortex and thalamus of mice showing signs of naloxone-precipitated withdrawal, while the expression of c-fos mRNA was significantly diminished by co-administration of DHEAS with morphine. On the naloxone-precipitated withdrawal, mice showed a significant elevation of cyclic AMP (cAMP) levels in the thalamus, whereas chronic administration of DHEAS with morphine did not affect the increase in cAMP. Interestingly, repeated co-administration of DHEAS with morphine prevented the withdrawal-induced phosphorylation of extracellular signal-regulated protein kinase (ERK) 2 in the frontal cortex. These results showed that DHEAS prevented the development of morphine tolerance and dependence and suggested that the attenuating effects of DHEAS might result from the regulation of c-fos mRNA expression, which is possibly involved the signaling activation of ERK, but not of cAMP pathway.