RESUMEN
Coffee consumption has been shown to reduce the risk of developing type 2 diabetes mellitus (T2DM) in humans; however, the exact mechanism is not completely understood. Here, we demonstrate that N-caffeoyltryptophan (CTP), an ingredient of coffee, enhances adipogenic differentiation and promotes glucose uptake into adipocytes. CTP increased lipid accumulation and adipogenic markers (PPARγ, C/EBPα, and FABP4) expression in mouse 3T3-L1 preadipocyte cell lines and primary preadipocytes. In addition, CTP promoted glucose uptake in 3T3-L1 cells. In the oral glucose tolerance test, daily administration of CTP (30 mg/kg/day, i.p.) for a week reduced blood glucose levels in mice. In 3T3-L1 cells, adipogenic differentiation and increased adipogenic markers expression induced by CTP were inhibited by U0126, a selective MEK1/2 inhibitor. Furthermore, mRNA induction of Pparg by CTP was abrogated in SIRT1 siRNA-transfected 3T3-L1 cells. These results suggest the involvement of the MEK/ERK signaling and SIRT1 in the mechanism of adipogenic function of CTP. Taken together, CTP might contribute to the reduction in postprandial glycemia and a subsequent reduction in onset risk for T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Sirtuina 1 , Humanos , Ratones , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Café , Diferenciación Celular , PPAR gamma/genética , GlucosaRESUMEN
(1) Background: Oenothein B, a cyclic dimeric ellagitannin present in various medicinal plants, has been reported to exert diverse effects that are beneficial for the treatment and prevention of diseases, including cancer and infections. We recently showed that oenothein B also functions in the brain because its oral administration to systemic inflammatory model mice reduced inflammatory responses in the brain and suppressed abnormal behavior. (2) Results: The present in vivo results demonstrated that oenothein B activated extracellular signal-regulated kinase 2 and cAMP response element-binding protein in the brain, both of which play important roles in synaptic transmission and learning/memory in the central nervous system (CNS). (3) Conclusions: These results suggest that oenothein B exerts neuroprotective effects on the CNS by not only its anti-inflammatory activity but also by enhancing neuronal signaling pathways.
RESUMEN
Citrus kawachiensis (Kawachi Bankan), is a citrus species grown in Ehime, Japan, and its peel is abundant in 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF). We have recently revealed that HMF, one of the citrus flavonoids, has anti-inflammatory activity and neuroprotective abilities in the brain against global cerebral ischemia. HMF rescued neuronal cell death in the hippocampus and suppressed the activation of microglia, whose activation have been shown to significantly aggravate neurological deficit scores for ischemic mice. In the Y-maze test, HMF showed protection against ischemia-induced short-term memory dysfunction; in addition, HMF enhanced the expression of brain-derived neurotrophic factor and accelerated neurogenesis in the hippocampus. Similarly, the powder of the peel of C. kawachiensis showed anti-inflammatory activity and neuroprotective abilities in the ischemic brain. To further examine the effect of the peel of C. kawachiensis, we administered it to senescence-accelerated-mouse prone 8 (SAMP8) mice, which show memory impairment and brain inflammation, tau hyperphosphorylation, and neuronal dysfunction. The C. kawachiensis treatment inhibited microglial activation and the hyperphosphorylation of tau protein in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in SAMP8. These results suggest that HMF and the peel of C. kawachiensis have potential effects as neuroprotective and anti-dementia agents.
Asunto(s)
Citrus/química , Demencia/tratamiento farmacológico , Flavonoides/farmacología , Flavonoides/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores , Nootrópicos , Fitoterapia , Animales , Antiinflamatorios , Isquemia Encefálica/complicaciones , Muerte Celular/efectos de los fármacos , Demencia/etiología , Modelos Animales de Enfermedad , Flavonoides/aislamiento & purificación , Hipocampo/metabolismo , Hipocampo/patología , Trastornos de la Memoria/etiología , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Proteínas tau/metabolismoRESUMEN
The elderly experience numerous physiological alterations. In the brain, aging causes degeneration or loss of distinct populations of neurons, resulting in declining cognitive function, locomotor capability, etc. The pathogenic factors of such neurodegeneration are oxidative stress, mitochondrial dysfunction, inflammation, reduced energy homeostatis, decreased levels of neurotrophic factor, etc. On the other hand, numerous studies have investigated various biologically active substances in fruit and vegetables. We focused on the peel of citrus fruit to search for neuroprotective components and found that: 1) 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) and auraptene (AUR) in the peel of Kawachi Bankan (Citrus kawachiensis) exert neuroprotective effects; 2) both HMF and AUR can pass through the blood-brain barrier, suggesting that they act directly in the brain; 3) the content of AUR in the peel of K. Bankan was exceptionally high, and consequently the oral administration of the dried peel powder of K. Bankan exerts neuroprotective effects; and 4) intake of K. Bankan juice, which was enriched in AUR by adding peel paste to the raw juice, contributed to the prevention of cognitive dysfunction in aged healthy volunteers. This review summarizes our studies in terms of the isolation/characterization of HMF and AUR in K. Bankan peel, analysis of their actions in the brain, mechanisms of their actions, and trials to develop food that retains their functions.
Asunto(s)
Citrus/química , Cumarinas/aislamiento & purificación , Flavonoides/aislamiento & purificación , Alimentos Funcionales , Fármacos Neuroprotectores/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Cumarinas/química , Flavonoides/química , Estructura Molecular , Fármacos Neuroprotectores/química , Extractos Vegetales/químicaRESUMEN
Walnut is a nutritious food material, but only a few studies have been conducted on the mechanisms of its functions and the technique for quality evaluation. Therefore, we analyzed the components in aqueous methanol extract of walnut, and characterized 30 components, including three new compounds, glansreginin C, ellagic acid 4-O-(3'-O-galloyl)-ß-D-xyloside, and platycaryanin A methyl ester. We analyzed the extracts of other nuts using HPLC and clarified that a characteristic peak corresponding to glansreginin A was mainly observed in walnut. These results suggested that glansreginin A might be an indicator component of the quality of walnut. We then examined whether glansreginin A has neuroprotective effect, using lipopolysaccharide (LPS)-induced inflammatory model mice. The results revealed that oral administration of glansreginin A prevented LPS-induced abnormal behavior and LPS-induced hyper-activation of microglia in the hippocampus. These results suggested that glansreginin A has the ability to exert neuroprotective effect via anti-inflammation in the brain.
Asunto(s)
Antiinflamatorios/farmacología , Juglans/química , Fármacos Neuroprotectores/farmacología , Valor Nutritivo , Extractos Vegetales/farmacología , Quinolinas/farmacología , Quinolonas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Ácido Elágico/farmacología , Hipocampo/patología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Lipopolisacáridos/farmacología , Masculino , Metanol/química , Éteres Metílicos/farmacología , Ratones , Ratones Endogámicos ICR , Microglía/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Quinolinas/uso terapéuticoRESUMEN
Caloric restriction (CR) is a major contributor to good health and longevity. CR mimetics (CRMs) are a group of plant-derived compounds capable of inducing the benefits of CR. Since a longevity gene, SIRT1, inhibits T-cell activation and SIRT1 loss results in increased T-cell activation, we hypothesized that compounds capable of activating SIRT1 signaling can inhibit T-cell activation and function as CRMs. Thus we propose, in the present study, the application of a T-cell activation-inhibitory assay to screen candidate CRMs. Well-known CRMs, such as resveratrol, butein, and fisetin, suppressed the anti-CD3/CD28 antibody-induced activation of mouse spleen T-cells. We next randomly assessed 68 plant-derived compounds for screening novel candidate CRMs using this bioassay and found that all four compounds showing IC50 values <5 µM, such as curcumin, α-mangostin, nobiletin, and heptamethoxyflavone, have beneficial functions for health such as anti-inflammatory effect. These results suggest that the T-cell activation-inhibitory assay can be used to screen candidate CRMs.
Asunto(s)
Inmunoensayo , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Biomarcadores , Restricción Calórica , Evaluación Preclínica de Medicamentos , Femenino , Inmunoensayo/métodos , Leucocitos/inmunología , Leucocitos/metabolismo , Ratones , Células RAW 264.7 , Transducción de Señal , Linfocitos T/efectos de los fármacosRESUMEN
Our previous study showed that the subcutaneous administration of auraptene (AUR) suppresses inflammatory responses including the hyperactivation of microglia in the substantia nigra (SN) of the midbrain of lipopolysaccharide-induced Parkinson's disease (PD)-like mice, as well as inhibits dopaminergic neuronal cell death in this region. We also showed that the oral administration of the dried peel powder of Citrus kawachiensis, which contains relatively high amounts of AUR, suppresses inflammatory responses including the hyperactivation of microglia in the systemically inflamed brain. In the present study we showed that the oral administration of this dried peel powder successfully suppressed microglial activation and protected against dopaminergic neuronal cell death in the SN, suggesting its potential as a neuroprotective agent for the treatment of patients with PD.
Asunto(s)
Muerte Celular/efectos de los fármacos , Citrus/química , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/metabolismo , Extractos Vegetales/farmacología , Animales , Peso Corporal , Modelos Animales de Enfermedad , Frutas/química , Inflamación/metabolismo , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Extractos Vegetales/administración & dosificaciónRESUMEN
Cerebral ischemia/reperfusion leads to delayed neuronal cell death, resulting in brain damage. Auraptene (AUR) and naringin (NGIN), which exert neuroprotective effects in ischemic brain, are abundant in the peel of Citrus kawachiensis. Although parts of AUR/NGIN are transited from the peel to the juice during the squeezing of this fruit, these amounts in juice might be too low to exert effects. We thus prepared the AUR/NGIN-rich fruit juice of C. kawachiensis by addition of peel paste to the raw juice. The present study revealed that orally administration of the dried powder of this AUR/NGIN-rich fruit juice (2.5 g/kg/d) for 7 d to ischemic mice significantly suppressed the ischemia-induced neuronal cell death in the hippocampus, which was coincidently with the reduction of hyperactivation of microglia and astrocytes. These results suggest that AUR/NGIN-rich juice of C. kawachiensis may possess therapeutic potential for the prevention of neurodegenerative diseases via inhibition of inflammatory processes.
Asunto(s)
Antiinflamatorios/farmacología , Isquemia Encefálica/tratamiento farmacológico , Citrus , Cumarinas/farmacología , Flavanonas/farmacología , Fitoterapia/métodos , Preparaciones de Plantas/farmacología , Animales , Encéfalo/metabolismo , Isquemia Encefálica/inducido químicamente , Muerte Celular/efectos de los fármacos , Cumarinas/administración & dosificación , Flavanonas/administración & dosificación , Jugos de Frutas y Vegetales , Hipocampo , Ratones , Fármacos Neuroprotectores/farmacología , PolvosRESUMEN
Cerebral ischemia/reperfusion is known to induce the generation of reactive oxygen species and inflammatory responses. Numerous studies have demonstrated that naringin (NGIN) has anti-oxidant and anti-inflammatory properties. We previously reported that Citrus kawachiensis contains a large quantity of NGIN in its peel. In the present study, we orally (p.o.) administered dried peel powder of C. kawachiensis to mice of a transient global ischemia model and found in the hippocampus region that it 1) suppressed neuronal cell death, 2) reversed the reduction in the level of phosphorylated calcium-calmodulin-dependent protein kinase II, 3) had the tendency to reverse the reduction in the level of glutathione, and 4) blocked excessive activation of microglia and astrocytes. These results suggested that the dried peel powder of C. kawachiensis had a neuroprotective effect against ischemic brain via anti-oxidative and anti-inflammatory effects. We also showed that these effects of the dried peel powder were more powerful than those obtained with a comparable amount of NGIN alone.
Asunto(s)
Isquemia Encefálica/prevención & control , Citrus/química , Flavanonas/farmacología , Hipocampo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Estructuras de las Plantas/química , Daño por Reperfusión/prevención & control , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Astrocitos/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Muerte Celular/efectos de los fármacos , Constricción Patológica , Modelos Animales de Enfermedad , Flavanonas/aislamiento & purificación , Glutatión/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Inflamación/etiología , Inflamación/prevención & control , Masculino , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , FosforilaciónRESUMEN
We previously reported that the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, exerted anti-inflammatory effects in the brain of a lipopolysaccharide-injected systemic inflammation animal model. Inflammation is one of the main mechanisms underlying aging in the brain; therefore, we herein evaluated the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the senescence-accelerated mouse-prone 8 (SAMP8) model. The C. kawachiensis treatment inhibited microglial activation in the hippocampus, the hyper-phosphorylation of tau at 231 of threonine in hippocampal neurons, and ameliorated the suppression of neurogenesis in the dentate gyrus of the hippocampus. These results suggest that the dried peel powder of C. kawachiensis exert anti-inflammatory and neuroprotective effects.
Asunto(s)
Envejecimiento , Citrus/química , Hipocampo/efectos de los fármacos , Microglía/metabolismo , Neurogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Estructuras de las Plantas/química , Proteínas tau/metabolismo , Animales , Antiinflamatorios/farmacología , Reacción de Prevención , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/prevención & control , Ratones , Fármacos Neuroprotectores/farmacología , FosforilaciónRESUMEN
In vitro screening methods using cultured Neuro2a cells to examine the activation (phosphorylation) of extracellular signal-regulated kinase (ERK) 1/2 and promotion of neurite outgrowth revealed that the extracts of 5 Kampo (Japanese traditional) formulations have potential as medicines for the treatment of behavioral abnormalities. Since sansoninto (SAT) extract exerted stronger effects than the other candidates tested, we investigated whether its oral administration ameliorates the pathologies of some mouse models of behavioral impairments. The results obtained suggested that SAT extract exerted anti-depression-like effects in the forced swim test, which may be mediated by the up-regulated expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. They may also be mediated by the enhanced phosphorylation of the cAMP response element-binding protein (CREB) via the mitogen-activated protein kinase (MAPK) cascade and Ca2+/calmodulin-dependent protein kinase II (CaMK II) cascade, a downstream signaling cascade of the N-methyl-D-aspartate (NMDA) receptor. These results indicate that the extract of SAT has potential as a new remedial medicine in the treatment of depression-like behavior.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Medicina Kampo/métodos , Animales , Japón , Masculino , RatonesRESUMEN
Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3',4'-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues to it was significantly higher than that of other citrus PMFs (nobiletin, tangeretin, and natsudaidain). The permeation of these PMFs into the brain well correlated with their abilities to suppress MK-801-induced locomotive hyperactivity, suggesting that HMF had the ability to act directly in the brain. We also obtained data suggesting that the suppressive effect of HMF on MK-801-induced locomotive hyperactivity was mediated by phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus.
Asunto(s)
Encéfalo/metabolismo , Maleato de Dizocilpina/efectos adversos , Flavonas/farmacología , Hipercinesia/inducido químicamente , Extractos Vegetales/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Cromatografía Líquida de Alta Presión , Citrus/química , Flavonas/administración & dosificación , Flavonas/química , Flavonas/farmacocinética , Hipocampo/metabolismo , Hipercinesia/tratamiento farmacológico , Inyecciones Intraperitoneales , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Permeabilidad , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Relación Estructura-ActividadRESUMEN
Wnt1-Cre- and Wnt1-GAL4 double transgenic (dTg) mice are used to study neural crest cell lineages by utilizing either the Cre/loxP or the GAL4/UAS system. We have previously shown that these mice exhibit behavioral abnormalities that resemble certain behaviors of psychiatric disorders and histologic alterations in the cholinergic and glutamatergic systems in the brain. The objective of the current study was to extend the behavioral analyses in these mice and to determine whether there were any sex-specific differences in the prevalence or severity of these behaviors. In the present study, we demonstrate additional behavioral abnormalities in dTg mice, such as increased locomotor activity, decreased social behavior, and an increased frequency in vertical jumping. Of these, the proclivity for vertical jumping was observed only in male dTg mice. In contrast, MK-801 administration induced increased locomotion in only female dTg mice. Furthermore, the concentrations of prolactin in the sera and oxytocin in the hypothalamus were both reduced only in female dTg mice, compared to controls. These sex-dependent behavioral and hormonal abnormalities in the dTG mice suggest that the phenotype of certain psychiatric disorders may be influenced by both genetic and sex-specific factors.
Asunto(s)
Modelos Animales de Enfermedad , Trastornos Mentales , Ratones Transgénicos , Fenotipo , Caracteres Sexuales , Comunicación Animal , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Hipotálamo/fisiopatología , Masculino , Conducta Materna , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/fisiopatología , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Oxitocina/metabolismo , Prolactina/sangre , Conducta Social , Conducta EstereotipadaRESUMEN
We investigated the effects of auraptene on mouse oligodendroglial cell lineage in an animal model of demyelination induced by cuprizone. Auraptene, a citrus coumarin, was intraperitoneally administered to mice fed the demyelinating agent cuprizone. Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone reduced immunoreactivity for myelin-basic protein, a marker of myelin, whereas it increased immunoreactivity to platelet derived-growth factor receptor-α, a marker of oligodendrocyte precursor cells. Administration of auraptene enhanced the immunoreactivity to oligodendrocyte transcription factor 2, a marker of oligodendrocyte precursor cells and oligodendrocyte lineage precursor cells, but had no effect on immunoreactivity to myelin-basic protein or platelet-derived growth factor receptor-α. These findings suggest that auraptene promotes the production of oligodendrocyte lineage precursor cells in an animal model of demyelination and may be useful for individuals with demyelinating diseases.
Asunto(s)
Cumarinas/farmacología , Enfermedades Desmielinizantes/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Oligodendroglía/efectos de los fármacos , Células Madre/efectos de los fármacos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Cuprizona , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Expresión Génica/efectos de los fármacos , Inyecciones Intraperitoneales , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteína Básica de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Células Madre/fisiologíaRESUMEN
Examination of the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, showed that it contained naringin (NGIN; 44.02 ± 0.491 mg/g), narirutin (NRTN; 4.46 ± 0.0563 mg/g), auraptene (AUR; 4.07 ± 0.033 mg/g), and 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF; 0.27 ± 0.0039 mg/g). When this dried peel powder was orally preadministered at the dose of 1.2 or 2.4 g/kg/day for 7 days into lipopolysaccharide- (LPS-) injected mice, an animal model of systemic inflammation, it suppressed (1) LPS-induced loss of body weight and abnormal behavior in the open field, (2) LPS-induced activation of microglia and astrocytes in the hippocampus, and (3) LPS-induced expression of cyclooxygenase (COX)-2, which were coexpressed in astrocytes of these mice. When NGIN or AUR was preadministered to LPS-injected mice at an amount similar to that in the peel powder, AUR, but not NGIN, had the ability to suppress the LPS-induced inflammation in the brain of these model mice. The dried powder of flavedo tissue (the outer colored layer of the mesocarp of a citrus fruit) and juice, which contained sufficient amounts of AUR, also had anti-inflammatory effect. These results suggest that AUR was the main ingredient responsible for the anti-inflammatory property of the dried peels of C. kawachiensis.
RESUMEN
The processing of sound information is mediated by the cochlea and the central auditory system. Among the central auditory system, the inferior colliculus (IC) has leading roles in the acoustic processing. In a previous study, we demonstrated psychiatric disorder-related behavioral abnormalities in a genetically modified animal of Wnt1-cre and Wnt1-GAL4 double-transgenic (dTg) mouse. Here we report an abnormal morphology of the IC and dysacusis in the dTg mice. The IC in the brain of the dTg mice is dilated in appearance and histologic analysis revealed a high cell-density in the IC. Also, the dTg mice showed high scores in a startle response test using a click box that emits a 20-kHz sound. Auditory brainstem response (ABR) test revealed lower ABR thresholds of the dTg mice at a test-stimulus frequency of 32kHz, but not at 4-16kHz. These findings suggest that the dTg mice could be a useful animal model for studying the physiologic function of the IC and the pathophysiology of psychiatric disorder-related dysacusis.
Asunto(s)
Modelos Animales de Enfermedad , Colículos Inferiores/anomalías , Reflejo de Sobresalto , Proteína Wnt1/genética , Estimulación Acústica , Animales , Recuento de Células , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Colículos Inferiores/fisiopatología , Masculino , Aprendizaje por Laberinto , Trastornos Mentales/patología , Trastornos Mentales/fisiopatología , Trastornos Mentales/psicología , Ratones Transgénicos , Actividad Motora , Cresta Neural/patología , Conducta Social , Percepción EspacialRESUMEN
Extracellular signal-regulated kinases 1/2 (ERK1/2), components of the mitogen-activated protein kinase (MAPK) signaling cascade, have been recently shown to be involved in synaptic plasticity and in the development of long-term memory in the central nervous system (CNS). We therefore examined the ability of Citrus compounds to activate ERK1/2 in cultured rat cortical neurons, whose activation might have a protective effect against neurodegenerative neurological disorders. Among the samples tested, extracts prepared from the peels of Citrus grandis (Kawachi bankan) were found to have the greatest ability to activate ERK1/2. The active substances were isolated by chromatographic separation, and one of them was identified to be 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF). HMF significantly induced the phosphorylation of cAMP response element-binding protein (CREB), a downstream target of activated ERK1/2, which appears to be a critical step in the signaling cascade for the structural changes underlying the development of long-term potentiation (LTP). In addition, the administration of HMF into mice treated with NMDA receptor antagonist MK-801 restored the MK-801-induced deterioration of spatial learning performance in the Morris mater-maze task. Taken together, these results suggest that HMF is a neurotrophic agent for treating patients with memory disorders.