RESUMO
Obesity is characterized by a condition of low-grade chronic inflammation that facilitates development of numerous comorbidities and dysregulation of brain homeostasis. It is reported that obesity can lead to behavioral alterations such as cognitive decline and depression-like behaviors both in humans and rodents. Saponins from panax japonicus (SPJ) have been reported to exhibit anti-inflammatory action in mouse model of diet-induced obesity. We evaluated the neuroprotection of SPJ on high fat diet (HFD) induced impaired behaviors such as memory deficit and depressive-like behaviors, and explored the underlying mechanisms. 6-week male Balb/c mice were divided into normal control group (NC, 17% total calories from fat), HFD group (60% total calories from fat), and HFD treated with SPJ groups (orally gavaged with dosages of 15 mg/kg and 45 mg/kg), respectively. After treatment for 16 weeks, behavioral tests were performed to evaluate the cognition and depression-like behaviors of the mice. The underling mechanisms of SPJ on HFD-induced impaired behaviors were investigated through histopathological observation, Western blot analysis and immunofluorescence. Our results showed that HFD-fed mice caused behavioral disorders, neuronal degeneration as well as elevated neuroinflammation, which was partly involved in NLRP3 inflammasome that finally resulted in decreased protein levels of AMPA receptors and down-regulated phosphorylated levels of CaMKII and CREB in cortex and hippocampus. All the above changes in cortex and hippocampus induced by HFD were mitigated by SPJ treatment. SPJ treatment alleviated HFD-induced recognitive impairment and depression-like behaviors of mice, which could be partly due to the capacity of SPJ to mitigate neuroinflammation through inhibition of NLRP3 inflammasome and upregulation of AMPA receptors signaling pathway.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Panax/química , Receptores de AMPA/biossíntese , Receptores de AMPA/efeitos dos fármacos , Saponinas/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Depressão/induzido quimicamente , Depressão/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Frankincense is an oleo gum resin derived from trees of genus Boswellia. It has favorable effects on memory formation. However, the probable underlying molecular mechanisms have not been assessed. Frankincense exerts some of its effects via activation of protein kinases. Calcium/calmodulin kinaseII (CaMKII) and CaMKIV are crucial mediators of learning and memory. We studied the effect of maternal injection of the aqueous extract of frankincense during gestation and lactation periods on spatial memory performance and the mRNA expression levels of the hippocampal CaMKIIand CaMKIV in the offspring rats. METHODS: Aqueous extract of Frankincense (50 and 100â¯mg/kg) or tap water was gavaged to distinct female rats during gestation and lactation periods. Memory performance was assessed in groups of male offspring using Morris water maze. In other groups of the offspring (with no memory test), the hippocampi of the juvenile rats were removed 30 days after labor. A real-time PCR method was used to measure the mRNA levels of CaMKII and CaMKIV. RESULTS: Frankincense improved spatial memory retrieval in the offspring rats in a dose-dependent manner. The mRNA expression of hippocampal CaMKIV was unchanged between groups. However, the mRNA expression of hippocampal CaMKII was dose-dependently upregulated in the rats, whose mothers had received frankincense. CONCLUSIONS: Due to the crucial role of the CaMKII in memory formation, the results provide a molecular basis for the effect of administration of frankincense to mother rats on improvement of the memory in the offspring.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Franquincenso/química , Hipocampo/metabolismo , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Animais , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/biossíntese , DNA Complementar/biossíntese , DNA Complementar/genética , Relação Dose-Resposta a Droga , Feminino , Hipocampo/efeitos dos fármacos , Lactação , Aprendizagem em Labirinto/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacosRESUMO
Stress is any condition that impairs the balance of the organism physiologically or psychologically. The response to stress involves several neurohormonal consequences. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and its release is increased by stress that predisposes to excitotoxicity in the brain. Memantine is an uncompetitive N-methyl D-aspartate glutamatergic receptors antagonist and has shown beneficial effect on cognitive function especially in Alzheimer's disease. The aim of the work was to investigate memantine effect on memory and behavior in animal models of acute and repeated restraint stress with the evaluation of serum markers of stress and the expression of hippocampal markers of synaptic plasticity. Forty-two male rats were divided into seven groups (six rats/group): control, acute restraint stress, acute restraint stress with Memantine, repeated restraint stress, repeated restraint stress with Memantine and Memantine groups (two subgroups as positive control). Spatial working memory and behavior were assessed by performance in Y-maze. We evaluated serum cortisol, tumor necrotic factor, interleukin-6 and hippocampal expression of brain-derived neurotrophic factor, synaptophysin and calcium-/calmodulin-dependent protein kinase II. Our results revealed that Memantine improved spatial working memory in repeated stress, decreased serum level of stress markers and modified the hippocampal synaptic plasticity markers in both patterns of stress exposure; in ARS, Memantine upregulated the expression of synaptophysin and brain-derived neurotrophic factor and downregulated the expression of calcium-/calmodulin-dependent protein kinase II, and in repeated restraint stress, it upregulated the expression of synaptophysin and downregulated calcium-/calmodulin-dependent protein kinase II expression.
Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hipocampo/efeitos dos fármacos , Memantina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Restrição Física/efeitos adversos , Memória Espacial/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Doença Aguda , Animais , Ansiedade/sangue , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/fisiologia , Biomarcadores/sangue , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Asseio Animal/efeitos dos fármacos , Asseio Animal/fisiologia , Hipocampo/química , Hipocampo/fisiopatologia , Hidrocortisona/sangue , Interleucina-6/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memantina/farmacologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Memória Espacial/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/sangue , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia , Sinaptofisina/biossíntese , Sinaptofisina/genética , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Neuroinflammation is considered to be a major factor in several neurodegenerative diseases. Recently, the polyunsaturated fatty acid omega-3 has been shown to have anti-inflammatory effects and might play an effective role in improving memory impairment due to inflammation. In order to test this, we stimulated neuroinflammation in an animal model and induced memory dysfunction as measured by reduced retention of passive avoidance learning (PAL) and altered expression of CaMKII-α, a gene known to be crucial for memory formation. We then investigated whether treatment with dietary omega-3 prevents inflammation-induced memory dysfunction in this model. METHODS: Male wistar rats (200-220 g) were fed either a control diet or a diet containing omega-3 (400mg/kg, po) for 1 month prior. Rats then received injection of either saline or LPS (500 µg/kg, ip) and were subjected to the PAL acquisition task. The retention test was performed 24h later, and animals were sacrificed immediately. Hippocampi were dissected and stored at -80°C. Finally, TNF-α levels and CaMKII-α gene expression were measured by ELISA and qRT-PCR, respectively. RESULTS: We found that LPS treatment significantly impaired PAL and memory, increased TNF-α levels and impaired CaMKII-α gene expression. In control and LPS-injected animals, pre-treatment with omega-3 improved performance on the PAL task and increased CAMKII-α gene expression. CONCLUSION: Taken together, these data suggest that dietary omega-3 may improve cognitive function and provide a potential therapy for memory impairment due to neuroinflammation.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Ácidos Graxos Ômega-3/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Transtornos da Memória/prevenção & controle , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Dieta , Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Transtornos da Memória/induzido quimicamente , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In the present study, withdrawal symptoms induced by morphine or ß-endorphin administered intracerebroventricularly (i.c.v.) were compared in ICR mice. Naloxone (10mg/kg) was post-treated intraperitoneally (i.p.) 3h after either a single or repeated (1 time/day for 3 days) i.c.v. injections with opioids. Withdrawal symptoms such as jumping frequency, diarrhea, weight loss, rearing, penile licking and paw tremor were observed for 30 min immediately after naloxone treatment. Withdrawal symptoms (jumping, diarrhea, weight loss, rearing, penile licking and paw tremor) observed in the group treated with morphine was persistently increased during 3 days. On the other hand, withdrawal symptoms such as diarrhea, weight loss and rearing in ß-endorphin-treated group were increased after a single injection with ß-endorphin, but gradually decreased after the repeated injection. Furthermore, no jumping behavior, penile licking and paw tremor in ß-endorphin-treated group were observed throughout the whole period of time. In addition, the hypothalamic changes of several signal molecules such as pERK, pCaMK-IIα, c-FOS and pCREB expression were observed during the presence or absence of withdrawal responses induced by morphine or ß-endorphin administered once or repeatedly. Both hypothalamic pCaMK-IIα and c-FOS expressions were increased by naloxone treatment in acutely administered morphine group, whereas only pCaMK-IIα expression was elevated by naloxone treatment in repeatedly administered morphine group. In contrast with the findings in morphine-treated group, only pCaMK-IIα expression was decreased by naloxone treatment in repeatedly administered ß-endorphin group. Our results suggest that profiles of the withdrawal symptoms induced by morphine and ß-endorphin administered supraspinally appear to be differentially regulated. The pCaMK-IIα and the c-FOS protein expression may play important roles for the regulation of naloxone-precipitated withdrawal symptoms such as jumping, diarrhea, weight loss, rearing, penile licking and paw tremor induced by morphine-treated group, whereas the phosphorylation of hypothalamic pCaMK-IIα appears to be involved only in the regulation of naloxone-precipitated withdrawal symptoms such as diarrhea, weight loss and rearing in ß-endorphin-treated group.
Assuntos
Hipotálamo/efeitos dos fármacos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Síndrome de Abstinência a Substâncias , beta-Endorfina/administração & dosagem , Animais , Western Blotting , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Hipotálamo/metabolismo , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-fos/biossíntese , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
Calcium is an essential signaling molecule in developing B cells, thus altering calcium dynamics represents a potential target for toxicant effects. GW7845, a tyrosine analog and potent peroxisome proliferator-activated receptor γ agonist, induces rapid mitogen-activated protein kinase (MAPK)-dependent apoptosis in bone marrow B cells. Changes in calcium dynamics are capable of mediating rapid initiation of cell death; therefore, we investigated the contribution of calcium to GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre-B cell line (BU-11) with GW7845 (40 µM) resulted in intracellular calcium release. Multiple features of GW7845-induced cell death were suppressed by the calcium chelator BAPTA, including MAPK activation, loss of mitochondrial membrane potential, cytochrome c release, caspase-3 activation, and DNA fragmentation. A likely mechanism for the calcium-mediated effects is activation of CaMKII, a calcium-dependent MAP4K. We observed that three CaMKII isoforms (ß, γ, and δ) are expressed in lymphoid tissues and bone marrow B cells. Treatment with GW7845 increased CaMKII activity. All features of GW7845-induced cell death, except loss of mitochondrial membrane potential, were suppressed by CaMKII inhibitors (KN93 and AIP-II), suggesting the activation of multiple calcium-driven pathways. To determine if CaMKII activation is a common feature of early B cell death following perturbation of Ca(2+) flux, we dissected tributyltin (TBT)-induced death signaling. High-dose TBT (1 µM) is known to activate calcium-dependent death. TBT induced rapid apoptosis that was associated with intracellular calcium release, CaMKII activation and MAPK activation, and was inhibited by AIP-II. Thus, we show that early B cells are susceptible to calcium-triggered cell death through a CaMKII/MAPK-dependent pathway.
Assuntos
Apoptose/fisiologia , Linfócitos B/metabolismo , Células da Medula Óssea/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Cálcio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Linhagem Celular , Quelantes/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Isoenzimas , Ligantes , MAP Quinase Quinase 4/biossíntese , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Oxazóis/farmacologia , Compostos de Trialquitina/farmacologia , Tirosina/análogos & derivados , Tirosina/farmacologiaRESUMO
Scutellarin is a flavonoid extracted from a traditional Chinese herb, Erigeron breviscapus Hand Mazz, which has been broadly used in treating various cardiovascular diseases. In this study, we investigated its effect on cardiac hypertrophy and the underlying mechanism. Both in vitro and in vivo cardiac hypertrophy models were employed to explore the anti-hypertrophic action of scutellarin. We found that scutellarin significantly suppressed the hypertrophic growth of neonatal cardiac myocytes exposed to phenylephrine (PE) and mouse heart subjected to pressure overload induced by aortic banding, accompanied with the decreased expression of hypertrophic markers beta-myosin heavy chain and atrial natriuretic peptide. We then measured the change of free intracellular calcium using laser scanning confocal microscope. We found that scutellarin alleviated the increment of free intracellular calcium during cardiac hypertrophy either induced by PE or aortic banding. The expression of calcium downstream effectors calcineurin and phosphorylated calmodulin kinase II (CaMKII) were significantly suppressed by scutellarin. Our study indicated that scutellarin exerts its anti-hypertrophic activity via suppressing the Ca(2+)-mediated calcineurin and CaMKII pathways, which supports the observation that clinical application of scutellarin is beneficial for cardiovascular disease patients.
Assuntos
Apigenina/farmacologia , Calcineurina/biossíntese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Cálcio/fisiologia , Glucuronatos/farmacologia , Vasodilatadores/farmacologia , Animais , Animais Recém-Nascidos , Apigenina/uso terapêutico , Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Glucuronatos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/uso terapêuticoRESUMO
The senescence-accelerated mouse prone-8 (SAMP8) is characterized by early onset of learning and memory deficits along with spontaneous overproduction of soluble beta-amyloid peptide (Abeta) in the brain. In our study, 4 month old male SAMP8 mice were orally administered 0.05% and 0.1% green tea catechins (GTC, w/v) in drinking water for 6 months. We found that a supplementation with 0.05% or 0.1% GTC prevented spatial learning and memory impairments of mice in the Morris water maze. Better performance of GTC-treated mice was associated with decreased levels of Abeta(1-42) oligomers in the hippocampus. The activity of the protein kinase A/cAMP-response element binding protein (PKA/CREB) pathway, one of the molecular targets of Abeta oligomers which is crucial for late long-term potentiation and long-term memory formation, was significantly increased after GTC administration. We also found that chronic 0.05% or 0.1% GTC consumption prevented the reductions of three representative proteins of synaptic function and synaptic structure, including brain-derived neurotrophic factor(BDNF), post-synaptic density protein-95 (PSD95) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). These results demonstrated that long-term 0.05% or 0.1% green tea catechin administration may prevent spatial learning and memory decline of SAMP8 mice by decreasing Abeta(1-42) oligomers and upregulating synaptic plasticity-related proteins in the hippocampus.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Catequina/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Proteínas de Membrana/biossíntese , Fragmentos de Peptídeos/metabolismo , Comportamento Espacial/efeitos dos fármacos , Envelhecimento , Animais , Camellia sinensis , Catequina/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal , Fosforilação , Sinapses/fisiologia , Fatores de Tempo , Regulação para CimaRESUMO
The effects of acute and chronic morphine treatments on the expression of Ca2+/calmodulin dependent protein kinase II (CaMK II) gene in rat brain were investigated using in situ hybridization histochemistry. Our data showed that repeated, but not single morphine administration, resulted in significant up-regulation of the alpha-CaMK II gene expression in hippocampus and frontal cortex. We further studied the time courses of alpha-CaMK II gene expression in response to repeated morphine administration. After 3 days of consecutive morphine injections, the alpha-CaMK II mRNA levels exhibited a trend of up-regulation, and after 6 days of consecutive morphine injections it increased over 50-60% as compared with the control group. The alpha-CaMK II mRNA levels remained high 24 h after the cessation of chronic morphine treatment and returned to the control level 72 h later. However, changes of alpha-CaMK II gene levels mentioned above were not detected in amygdala or piriform cortex. Taken together, our data demonstrate that chronic morphine treatment region-specific up-regulates the levels of the alpha-CaMK II gene expression in hippocampus and frontal cortex.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Morfina/administração & dosagem , Animais , Esquema de Medicação , Lobo Frontal/enzimologia , Hipocampo/enzimologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
Gonadotropin-releasing hormone (GnRH) is secreted from hypothalamic GnRH neurons. There is accumulating evidence that GnRH neurons have GnRH receptors and that the autocrine action of GnRH activates MAP kinase. In this study, we found that KN93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinases (CaM kinases), inhibited the GnRH-induced activation of MAP kinase in immortalized GnRH neurons (GT1-7 cells). Immunoblot analysis indicated that the CaM kinase IIdelta2 isoform (CaM kinase IIdelta2) and synapsin I were expressed in GT1-7 cells. GnRH treatment rapidly increased phosphorylation of synapsin I at serine 603, a specific phosphorylation site for CaM kinase II, suggesting that GnRH treatment rapidly activated CaM kinase IIdelta2. In addition, when we stably overexpressed CaM kinase IIdelta2 in GT1-7 cells, the activation of MAP kinase was strongly enhanced. These results suggest that CaM kinase IIdelta2 was involved in the GnRH-induced activation of MAP kinase in GT1-7 cells.