RESUMO
Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment.
Assuntos
Região CA1 Hipocampal , Dendritos , Diterpenos do Tipo Caurano , Potenciação de Longa Duração , Animais , Feminino , Masculino , Região CA1 Hipocampal/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Camundongos , Dendritos/efeitos dos fármacos , Memória/efeitos dos fármacos , Fatores Sexuais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologiaRESUMO
Curcumin is a polyphenol substance considered to be effective in the treatment of a number of neurodegenerative diseases. However, details regarding the exact mechanisms for the protective effects of curcumin in neuropsychiatric disorders, like depression, remain unknown. In the pathogenesis of major depressive disorder (MDD) it appears that dysregulation of oxidative stress and immune systems, particularly within the hippocampal region, may play a critical role. Here, we show that pre-treatment with curcumin (40 mg kg-1) alleviates depression-like behaviors in a LPS-induced rat model of depression, effects which were accompanied with suppression of oxidative stress and inflammation and an inhibition of neuronal apoptosis in the hippocampal CA1 region, and results from ultramicrostructure electrophysiological experiments revealed that the curcumin pre-treatment significantly prevented excessive synaptic loss and enhanced synaptic functioning in this LPS-induced rat model. In addition, curcumin attenuated the increases in levels of miR-146a-5p and decreases in the expression of p-ERK signaling that would normally occur within CA1 regions of these depressed rats. Taken together, these results demonstrated that curcumin exerts neuroprotective and antidepressant activities by suppressing oxidative stress, neural inflammation and their related effects upon synaptic dysregulation. One of the mechanisms for these beneficial effects of curcumin appears to involve the miR-146a-5p/ERK signaling pathway within the hippocampal CA1 region. These findings not only elucidated some of the mechanisms underlying the neuroprotective/antidepressant effects of curcumin, but also suggested a role of curcumin as a potential therapeutic strategy for depression.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Curcumina/farmacologia , Depressão/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Região CA1 Hipocampal/citologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos WistarRESUMO
Protective effects of Puerariae flos extract (PFE) on ethanol (EtOH) exposure have been previously verified. This study attempts to explore the protective effects of PEF on EtOH withdrawal models. Sixty male Kunming mice were involved which were randomly divided into five groups (intact control, EtOH group (35-day EtOH exposure), EtOH withdrawal group (28-day exposure + 7-day withdrawal), EtOH withdrawal group + positive control (Deanxit) group, and EtOH withdrawal group + PFE group). The changes of neuropsychological behaviors; hippocampal BDNF expression and CA1 neuronal density; and plasma corticotropin-releasing hormone (CRH), ACTH, and CORT levels were observed. It was found that depression-like behaviors reduced by EtOH exposure and increased by withdrawal under the 28-day EtOH exposure and 7-day withdrawal conditions. In addition, anxiety-like behaviors worsened by EtOH exposure and unchanged by withdrawal. Deanxit and PEF ameliorated such behaviors (vs. withdrawal group). Hippocampal BDNF expression was significantly downregulated by EtOH exposure and upregulated by withdrawal. Deanxit and PEF significantly upregulated the BDNF expression. The hippocampal CA1 neuronal density significantly decreased by EtOH exposure but unchanged by withdrawal and treatments. The plasma CRH, ACTH, and CORT levels show a significant enhancement by EtOH exposure and reduced by withdrawal. They were further reduced by Deanxit and PEF. The protective effects of PEF on EtOH chronic withdrawal mouse models were verified. The results of this study also indicated a complicated scenario of neuropsychological behaviors, hippocampal BDNF expression, and hypothalamic-pituitary-adrenal axis which are affected by the timing of EtOH exposure and withdrawal.
Assuntos
Alcoolismo/tratamento farmacológico , Ansiedade/prevenção & controle , Região CA1 Hipocampal/efeitos dos fármacos , Depressão/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Pueraria , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Alcoolismo/metabolismo , Alcoolismo/patologia , Alcoolismo/psicologia , Animais , Ansiedade/metabolismo , Ansiedade/patologia , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Hormônio Liberador da Corticotropina/sangue , Depressão/metabolismo , Depressão/patologia , Depressão/psicologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Masculino , Camundongos , Pueraria/química , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
PURPOSE: The study evaluated the neuroprotective effect and pharmacokinetic profile of turmeric extract and their metabolites in the blood and brain in an aluminum-induced neurotoxic animal model. METHODS: Swiss albino mice received turmeric extract (TE), TE-essential oil combination (TE+EO) at doses of 25 and 50 mg/kg/day orally, vehicle (control), and a positive control group. Neurotoxicity was induced by injecting aluminum chloride (40 mg/kg/day, i.p.), and the effect of the intervention was studied for 45 days. The pharmacokinetic and behavioral biochemical markers of brain function and brain histopathological changes were evaluated. RESULTS: The AUC 0-t showed a 30.1 and 54.2 times higher free curcumin concentration in plasma with 25 mg/kg and 50 mg/kg of TE+EO vs. TE, respectively. The concentration of free curcumin in the brain was 11.01 and 13.71-fold higher for 25 mg/kg and 50 mg/kg of TE+EO vs. TE, respectively. Aluminum impairs spatial learning and memory, which was significantly reversed with TE+EO by 28.6% (25 mg/kg) and 39.4% (50 mg/kg). In the elevated plus maze test, 44.8% (25 mg/kg) and 67.1% (50 mg/kg) improvements were observed. A significant reduction in aluminum-induced lipid peroxidation was observed. Also, the levels of glutathione, acetylcholinesterase, and catalase were improved with TE+EO. Damage to the hippocampal pyramidal cells was averted with TE+EO. CONCLUSION: The neuroprotective and antioxidant response confirms the benefits of TE+EO against aluminum-induced neurotoxicity. The presence of free curcumin and its metabolites in the brain and plasma establishes its improved bioavailability and tissue distribution. Therefore, the benefits of TE+EO could be harnessed in neurodegenerative diseases.
Assuntos
Encéfalo , Curcuma , Fármacos Neuroprotetores , Extratos Vegetais , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Curcumina , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Óleos Voláteis/farmacocinética , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Distribuição TecidualRESUMO
Gynura procumbens has been used in Southeast Asia for the treatment of hypertension, hyperglycemia, and skin problems induced by ultraviolet irradiation. Although considerable studies have reported the biological properties of Gynura procumbens root extract (GPE-R), there are no studies on the effects of GPE-R in brain damages, for example following brain ischemia. In the present study, we screened the neuroprotective effects of GPE-R against ischemic damage and neuroinflammation in the hippocampus based on behavioral, morphological, and biological approaches. Gerbils received oral administration of GPE-R (30 and 300 mg/kg) every day for three weeks and 2 h after the last administration, ischemic surgery was done by occlusion of both common carotid arteries for 5 min. Administration of 300 mg/kg GPE-R significantly reduced ischemia-induced locomotor hyperactivity 1 day after ischemia. Significantly more NeuN-positive neurons were observed in the hippocampal CA1 regions of 300 mg/kg GPE-R-treated animals compared to those in the vehicle-treated group 4 days after ischemia. Administration of GPE-R significantly reduced levels of pro-inflammatory cytokines such as interleukin-1ß, -6, and tumor necrosis factor-α 6 h after ischemia/reperfusion. In addition, activated microglia were significantly decreased in the 300 mg/kg GPE-R-treated group four days after ischemia/reperfusion compared to the vehicle-treated group. These results suggest that GPE-R may be one of the possible agents to protect neurons from ischemic damage by reducing inflammatory responses.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Animais , Peso Corporal , Isquemia Encefálica/patologia , Isquemia Encefálica/cirurgia , Região CA1 Hipocampal/patologia , Citocinas , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Gerbillinae , Hipocampo/efeitos dos fármacos , Masculino , Microglia , Traumatismo por Reperfusão/patologiaRESUMO
Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/metabolismo , Inseticidas/toxicidade , Nitrilas/toxicidade , Piretrinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Disruptores Endócrinos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurônios/patologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Caracteres SexuaisRESUMO
Vascular dementia (VaD) is widely recognized as the second most common type of dementia, yet effective treatments are still lacking. Traditional Chinese medicine Yi-Gan San (YGS) has potent efficacy on treating VaD in clinical practice. However, the underlying mechanism is still unclear. In the present study, a UPLC-QTOFMS-based metabolomic method was established to explore the therapeutic mechanisms of YGS on VaD. Experimental VaD model was induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2-VO]) in rats. Cognitive function, pathological changes and oxidative stress condition in the brains of VaD rats were assessed using Morris water maze tests, hematoxylin-eosin staining and antioxidant assays (MDA, SOD, GSH and GSH-Px), respectively. UPLC-QTOFMS combined with computational systems analysis were conducted to study the changes of metabolic networks in serum of rats. The results indicated that VaD model was established successfully and 2-VO caused a decline in spatial learning and memory and hippocampal histopathological abnormalities of rats. YGS significantly improved the cognitive impairment induced by 2VO and attenuated hippocampal histopathological abnormalities. The inducement of 2-VO significantly elevated the level of MDA, and reduced SOD and GSH-Px activities, and YGS can significantly regulate the levels. We have identified 34 significantly changed metabolites related to 2-VO-induced VaD, and YGS can significantly regulate the abnormalities of 24 metabolites. Metabolic pathway enrichment analysis revealed that the mechanisms of YGS against 2-VO-induced VaD may be attributed to modulating the metabolic disorders of arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and sphingolipid metabolism. The present study provides new experimental information on the pathogenesis of VaD, unravels the potential targeted metabolic pathways of YGS against VaD on the whole metabolic network and highlights the importance of metabolomics as a potential tool for deciphering drug-targeted metabolic pathways.
Assuntos
Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Tradicional Chinesa , Metabolômica , Animais , Antioxidantes/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Lingonberries (LB) have been shown to have beneficial metabolic effects, which is associated with an altered gut microbiota. This study investigated whether the LB-induced improvements were associated with altered gut- and neuroinflammatory markers, as well as cognitive performance in ApoE-/- mice fed high-fat (HF) diets. Whole LB, as well as two separated fractions of LB were investigated. Eight-week-old male ApoE-/- mice were fed HF diets (38% kcal) containing whole LB (wLB), or the insoluble (insLB) and soluble fractions (solLB) of LB for 8 weeks. Inclusion of wLB and insLB fraction reduced weight gain, reduced fat deposition and improved glucose response. Both wLB and insLB fraction also changed the caecal microbiota composition and reduced intestinal S100B protein levels. The solLB fraction mainly induced weight loss in the mice. There were no significant changes in spatial memory, but significant increases in synaptic density in the hippocampus were observed in the brain of mice-fed wLB and insLB. Thus, this study shows that all lingonberry fractions counteracted negative effects of HF feedings on metabolic parameters. Also, wLB and insLB fraction showed to potentially improve brain function in the mice.
Assuntos
Encéfalo/efeitos dos fármacos , Encefalite/prevenção & controle , Gastrite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Vaccinium vitis-Idaea , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Dieta Hiperlipídica , Ácidos Graxos Voláteis , Metabolismo dos Lipídeos , Masculino , Camundongos Knockout para ApoE , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Sinapses/efeitos dos fármacosRESUMO
Creatine plays a crucial role in developing the brain, so much that its genetic deficiency results in mental dysfunction and cognitive impairments. Moreover, creatine supplementation is currently under investigation as a preventive measure to protect the fetus against oxidative stress during difficult pregnancies. Although creatine use is considered safe, posing minimal risk to clinical health, we found an alteration in morpho-functional maturation of neurons when male rats were exposed to creatine loads during brain development. In particular, increased excitability and enhanced long-term potentiation (LTP) were observed in the hippocampal pyramidal neurons of weaning pups. Since these effects were observed a long time after creatine treatment had been terminated, long-lasting modifications persisting into adulthood were hypothesized. Such modifications were investigated in the present study using morphological, electrophysiological, and calcium imaging techniques applied to hippocampal Cornu Ammonis 1 (CA1) neurons of adult rats born from dams supplemented with creatine. When compared to age-matched controls, the treated adult offspring were found to retain enhanced neuron excitability and an improved LTP, the best-documented neuronal substrate for memory formation. While translating data from rats to humans does have limitations, our findings suggest that prenatal creatine supplementation could have positive effects on adult cognitive abilities.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Creatina/administração & dosagem , Suplementos Nutricionais , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Células Piramidais/efeitos dos fármacos , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA1 Hipocampal/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cognição/efeitos dos fármacos , Feminino , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Memória/efeitos dos fármacos , Gravidez , Células Piramidais/metabolismo , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The chemical constituents and action targets of Acori Tatarinowii Rhizoma and Curcumae Radix were screened by network pharmacological method,and the mechanism of the combination of Acori Tatarinowii Rhizoma and Curcumae Radix in the treatment of epilepsy was analyzed. All chemical constituents of Acori Tatarinowii Rhizoma and Curcumae Radix were retrieved by TCMSP,and their action targets were screened. Component target PPI network was constructed. Epilepsy-related genes were retrieved from PharmGkb database,and PPI networks of disease targets were drawn by Cytoscape software. Cytoscape software was used to merge the network,screen the core network,and further analyze the gene GO function and KEGG pathway enrichment,which was verified by experimental research. One hundred and five chemical constituents of Acori Tatarinowii Rhizoma and 222 chemical constituents of Curcumae Radix were retrieved. Nineteen compounds were selected as candidate compounds according to OB and DL values. Among them,4 chemical constituents of Acori Tatarinowii Rhizoma and 15 chemical constituents of Curcumae Radix were found. A total of 88 target proteins were retrieved by retrieving TCMSP data,and PPI network was constructed. Through PharmGkb database,29 epilepsy-related genes were retrieved and disease target network was established. Cytoscape software and plug-ins were used for network merging and core network screening,and 69 genes were screened out. Through GO function analysis and KEGG pathway analysis,the mechanism of anti-epilepsy is related to prolactin signaling pathway,HTLV-â infection signaling pathway,MAPK signaling pathway and herpes simplex infection signaling pathway. Further experimental verification showed that the serum prolactin level in epileptic rats was significantly increased. The neurons in hippocampal CA1 area degenerated,necrotized and lost 24 hours after epileptic seizure,and some neuron interstitial edema occurred. The possible mechanism of compatibility of Acori Tatarinowii Rhizoma and Curcumae Radix is related to serum prolactin level,MAPK signaling pathway,HTLV-â infection and herpes simplex infection. The analysis may be related to viral encephalitis caused by HTLV-â virus and herpes simplex infection,which damages nerve cells and causes seizures.
Assuntos
Acorus/química , Curcuma/química , Medicamentos de Ervas Chinesas/farmacologia , Epilepsia/tratamento farmacológico , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Hipocampo , Raízes de Plantas/química , Ratos , Rizoma/químicaRESUMO
To examine the effects of Populus tomentiglandulosa (PT) extract on the expressions of antioxidant enzymes and neurotrophic factors in the cornu ammonis 1 (CA1) region of the hippocampus at 5 min after inducing transient global cerebral ischemia (TGCI) in gerbils, TGCI was induced by occlusion of common carotid arteries for 5 min. Before ischemic surgery, 200 mg·kg-1 PT extract was orally administrated once daily for 7 d. We performed neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B staining. Furthermore, we determined in situ production of superoxide anion radical, expression levels of SOD1 and SOD2 as antioxidant enzymes and brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I) as neurotrophic factors. Pretreatment with 200 mg·kg-1 PT extract prevented neuronal death (loss). Furthermore, pretreatment with 200 mg·kg-1 PT extract significantly inhibited the production of superoxide anion radical, increased expressions of SODs and maintained expressions of BDNF and IGF-I. Such increased expressions of SODs were maintained in the neurons after IRI. In summary, pretreated PT extract can significantly increase levels of SODs and protect the neurons against TGCI, suggesting that PT can be a useful natural agent to protect against TGCI.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Extratos Vegetais/administração & dosagem , Populus/química , Células Piramidais/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/metabolismo , Gerbillinae , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , Fármacos Neuroprotetores/administração & dosagem , Células Piramidais/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/genética , Regulação para Cima/efeitos dos fármacosRESUMO
Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).
Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Panax/química , Animais , Isquemia Encefálica/induzido quimicamente , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Cobalto/toxicidade , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Células PC12 , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/induzido quimicamente , Traumatismo por Reperfusão/tratamento farmacológico , Sirtuína 1/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: The purpose of this study was to investigate the effects of yokukansan on forebrain ischemia. Because we can measure nitric oxide production and hydroxyl radical metabolism continuously, we investigated the effect of yokukansan on nitric oxide production and hydroxyl radical metabolism in cerebral ischemia and reperfusion. METHODS: Yokukansan (300 mg per kg per day) was mixed into feed and given to 16 mice for 10days. Sixteen additional mice received normal feed (control). Nitric oxide production and hydroxyl radical metabolism were continuously monitored using the salicylate trapping method. Forebrain ischemia was producedin all mice by occluding the common carotid artery bilaterally for 10minutes. Levels of the nitric oxide metabolites nitrite and nitrate were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine-immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72hours after the start of reperfusion. RESULTS: Arterial blood pressure and regional cerebral blood flow were not significantly different between the 2 groups. The level of nitrate was significantly higher in the yokukansan group than in the control group during ischemia and reperfusion. Levels of 2,3- and 2,5-dihydroxybenzoic acid were significantly lower in the yokukansan group than in the control group during ischemia and reperfusion. Although survival rates in the CA1 did not differ significantly, there were fewer 8-hydroxydeoxyguanosine-immunopositive cells in animals that had received yokukansan than in control animals. CONCLUSIONS: These data suggest that yokukansan exerts reducing hydroxyl radicals in cerebral ischemic injury.
Assuntos
Antioxidantes/farmacologia , Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Radical Hidroxila/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fatores de TempoRESUMO
OBJECTIVE: Zhike-Houpu herbal pair (ZKHPHP) is a well-known Chinese medicine to treat gastrointestinal motility dysfunction. Recently, many researchers have found that some of the compounds of ZKHPHP such as meranzin hydrate and magnolol have antidepressant effects. However, little is known about the antidepressant mechanism of ZKHPHP. Therefore, the main aim of the study is to evaluate the antidepressant-like effects of ZKHPHP and its possible mechanism of action on 5-hydroxytryptamine receptor 1A (HTR1A) in the hippocampus CA1 region in rats exposed to chronic unpredictable mild stress. METHODS: Male Sprague Dawley rats were randomly divided into the following six groups: normal, model, ZKHPHP (3 g/kg), ZKHPHP (10 g/kg), ZKHPHP (20 g/kg), and ZKHPHP (30 g/kg); n = 8 per group. We exposed the rats to chronic unpredictable mild stress and then assessed antidepressant-like effects of ZKHPHP by measuring weight change, observing the open-field test, and measuring sucrose water consumption. The antidepressant mechanism was examined by measuring the effect of ZKHPHP on HTR1A protein expression and HTR1A mRNA expression in the hippocampus CA1 region by using immunohistochemistry analysis, Western blotting, and real-time reverse transcription-polymerase chain reaction. RESULTS: ZKHPHP (10 or 20 g/kg) reduced the incidence of depressive-like behaviors and increased HTR1A protein and HTR1A mRNA expression in the hippocampus CA1 in rats displaying depressive behavior, whereas ZKHPHP (3 or 30 g/kg) had no obvious effect on the measured depression indicators. CONCLUSIONS: These data show that ZKHPHP has antidepressant-like effects based on a chronic unpredictable mild stress-induced depression model in rats. ZKHPHP may be attractive as an antidepressant because of its beneficial effects on depression and the absence of gastrointestinal dysregulation, which is a frequently observed unintended effect of many commonly used antidepressive medications.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Magnolia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Estresse Psicológico/complicações , Animais , Antidepressivos/administração & dosagem , Depressão/etiologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Medicina Tradicional Chinesa , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Cholesterol, a critical component of the cellular plasma membrane, is essential for normal neuronal function. Cholesterol content is highest in the brain, where most cholesterol is synthesized de novo; HMG-CoA reductase controls the synthesis rate. Despite strict control, elevated blood cholesterol levels are common and are associated with various neurological disorders. G protein-gated inwardly rectifying potassium (GIRK) channels mediate the actions of inhibitory brain neurotransmitters. Loss of GIRK function enhances neuron excitability; gain of function reduces neuronal activity. However, the effect of dietary cholesterol or HMG-CoA reductase inhibition (i.e., statin therapy) on GIRK function remains unknown. Using a rat model, we compared the effects of a high-cholesterol versus normal diet both with and without atorvastatin, a widely prescribed HMG-CoA reductase inhibitor, on neuronal GIRK currents. The high-cholesterol diet increased hippocampal CA1 region cholesterol levels and correspondingly increased neuronal GIRK currents. Both phenomena were reversed by cholesterol depletion in vitro. Atorvastatin countered the high-cholesterol diet effects on neuronal cholesterol content and GIRK currents; these effects were reversed by cholesterol enrichment in vitro. Our findings suggest that high-cholesterol diet and atorvastatin therapy affect ion channel function in the brain by modulating neuronal cholesterol levels.
Assuntos
Atorvastatina/farmacologia , Colesterol na Dieta/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
This paper was aimed to investigate the effect of gastrodin( GAS) on hippocampal neurogenesis after cerebral was chemic and to explore its mechanism of action related to NO. The cerebral ischemia model of C57 BL/6 mice was established by bilateral common carotid artery occlusion. The pathological changes in hippocampal CA1 region and the cognitive function of mice were assessed by HE staining and Morris water maze test,respectively. The count of Brd U/Neu N positive cells in dentate gyrus was detected by immunofluorescence assay. The NOS activity and the NO content were determined by colorimetric and nitrate reduction methods,respectively.The level of c GMP was measured by ELISA kit,and the PKG protein expression was tested by Western blot. On postoperative day 8,the hippocampal CA1 pyramidal neurons of mice showed irregular structure,with obvious nuclear pyknosis,loose cell arrangement and obvious decrease in the number of neurons. On postoperative day 29,the spatial learning ability and memory were decreased. These results indicated cerebral ischemia in mice. Meanwhile,the Brd U/Neu N positive cells were increased significantly in ischemic mice,indicating that neurogenesis occurred in hippocampus after cerebral ischemia. Treatment with different doses of gastrodin( 50 and 100 mg·kg-1) significantly ameliorated the pathological damages in the CA1 region,improved the ability of learning and memory,and promoted hippocampal neurogenesis. At the same time,both the NOS activity and the NO concentration were decreased in model group,but the c GMP level was increased,and the PKG protein expression was up-regulated. Gastrodin administration activated the NOS activity,promoted NO production,further increased c GMP level and up-regulated PKG protein expression. These results suggested that gastrodin can promote hippocampal neurogenesis after cerebral ischemia and improve cognitive function in mice,which may be related to the activation of NO-cGMP-PKG signaling pathway.
Assuntos
Álcoois Benzílicos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Glucosídeos/uso terapêutico , Neurogênese , Transdução de Sinais , Animais , Cognição , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To investigate the role of Eclipta prostrata (E. prostrata) extract in improving spatial learning and memory deficits in D-galactose-induced aging in rats. METHODS: Rats were divided into five groups, with 10 animals in each group. Aging rats were produced by treatment with 100 mg·kg-1·d-1 of D-galactose for 6 weeks. Rats in the E. prostrata treatment groups received an aqueous extract of E. prostrata orally at a concentration of 50, 100, or 200 mg·kg-1·d-1 for 3 weeks. Animals in both the normal and model groups were treated with similar volumes of saline. Spatial memory performance was measured using the Morris water maze. The mRNA levels and enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were analyzed using real-time quantitative PCR and spectrophotometry, respectively. The levels of induced nitric oxide synthase (iNOS), nitric oxide (NO), dopamine (DA), norepinephrine (NE), and serotonin (5-HT) were determined using enzyme-linked immunosorbent assay and spectrophotometry. RESULTS: Compared with the normal group, rats in the D-galactose-treated model group exhibited significant memory loss. There was severe damage to the hippocampal CA1 area, and expression levels of SOD, CAT, GPx, and GR were significantly decreased in the model group compared with the normal group. In the model group, levels of iNOS and NO were significantly increased compared with the normal group. However, treatment with E. prostrata extract reversed the conditions caused by D-galactose-induced aging, especially in the groups with higher treatment concentrations. Compared with the normal group, the levels of DA, NE, and 5-HT were significantly lower in the D-galactose-treated model group. In the E. prostrata extract-treated groups, however, there was a dose-dependent upregulation of DA, NE, and 5-HT expression. CONCLUSION: Our results suggest that administration of E. prostrata extract can result in an improvement in the learning and memory impairments that are induced by D-galactose treatment in rats. This improvement may be the result of enhanced antioxidative ability, decreased iNOS and NO levels, and the induction of DA, NE, and 5-HT expression in the brain.
Assuntos
Envelhecimento/efeitos dos fármacos , Eclipta/química , Galactose/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Extratos Vegetais/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Catalase/genética , Dopamina/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/genética , Glutationa Redutase/genética , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Norepinefrina/metabolismo , Extratos Vegetais/uso terapêutico , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Superóxido Dismutase/genéticaRESUMO
Cognitive impairments can be devastating for quality of life, and thus, preventing or counteracting them is of great value. To this end, the present study exploits the potential of the plant Rhodiola rosea and identifies the constituent ferulic acid eicosyl ester [icosyl-(2E)-3-(4-hydroxy-3-methoxyphenyl)-prop-2-enoate (FAE-20)] as a memory enhancer. We show that food supplementation with dried root material from R. rosea dose-dependently improves odor-taste reward associative memory scores in larval Drosophila and prevents the age-related decline of this appetitive memory in adult flies. Task-relevant sensorimotor faculties remain unaltered. From a parallel approach, a list of candidate compounds has been derived, including R. rosea-derived FAE-20. Here, we show that both R. rosea-derived FAE-20 and synthetic FAE-20 are effective as memory enhancers in larval Drosophila. Synthetic FAE-20 also partially compensates for age-related memory decline in adult flies, as well as genetically induced early-onset loss of memory function in young flies. Furthermore, it increases excitability in mouse hippocampal CA1 neurons, leads to more stable context-shock aversive associative memory in young adult (3-month-old) mice, and increases memory scores in old (>2-year-old) mice. Given these effects, and given the utility of R. rosea-the plant from which we discovered FAE-20-as a memory enhancer, these results may hold potential for clinical applications.
Assuntos
Ácidos Cumáricos/farmacologia , Ésteres/farmacologia , Memória/efeitos dos fármacos , Rhodiola/química , Fatores Etários , Animais , Abelhas , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Suplementos Nutricionais , Drosophila melanogaster , Medo/efeitos dos fármacos , Larva/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Especificidade da EspécieRESUMO
Low frequency stimulation (LFS) has been proposed as a method in the treatment of epilepsy, but its anticonvulsant mechanism is still unknown. In the current study, the hippocampal CA1 region was microinjected with NAD-299 (a selective 5-HT1A antagonist), and its role in mediating the inhibitory action of LFS on amygdala kindling was investigated. Male Wistar rats were kindled by amygdala stimulation in a semi-rapid kindling manner (12 stimulations per day). LFS (0.1â¯ms pulse duration at 1â¯Hz, 200 pulses, 50-150⯵A) was applied at 5â¯min after termination of daily kindling stimulations. NAD (a selective 5-HT1A antagonist) was microinjected into the CA1 region of the hippocampus at the doses of 2.5 and 5⯵g/1⯵l. An open field test was also run to determine the motor activity of animals in different experimental groups. The application of LFS following daily kindling stimulations reduced the behavioral seizure stages, afterdischarge duration, and stage 5 seizure duration and increased the latency to stage 4 seizure compared to the kindled group. However, microinjection of NAD at the doses of 5⯵g/1⯵l, but not 2.5⯵g/1⯵l, blocked the inhibitory effect of LFS on behavioral and electrophysiological parameters in kindled animals. It could be presumed that 5-HT1A receptors in the CA1 area are involved in mediating the antiepileptic effects of LFS.
Assuntos
Região CA1 Hipocampal/metabolismo , Terapia por Estimulação Elétrica , Receptor 5-HT1A de Serotonina/metabolismo , Convulsões/metabolismo , Convulsões/terapia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Benzopiranos/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Neuroestimuladores Implantáveis , Excitação Neurológica , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos Wistar , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
BACKGROUND: It is well known that Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-ß (Aß) deposition and synaptic dysfunction play important roles in the pathophysiology of Alzheimer's disease (AD). The Huatuo Zaizao pill (HT) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China, mainly for post-stroke rehabilitation and cognitive decline; however, the mechanism of cognitive function is not clear. In this study, we investigated the effect of HT on hippocampal synaptic function, Amyloid-ß (Aß) deposition in APP/PS1 AD transgenic mice. METHOD: Six-month-old APP/PS1 transgenic (Tg) mice were randomly divided into control, HT-treated, and memantine (MEM)-treated groups. Then, these groups were orally administered vehicle (for the control), HT (0.25 g/kg) and MEM (5 mg/kg) respectively for 4 weeks. The Morris water maze, Novel Object Recognition, and Open field tests were used to assess cognitive behavioral changes. We evaluated the effects of HT on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular tests. Synaptic morphology in the hippocampus was investigated by electron microscopy. Western blotting was used to assess synaptic-associated protein and Aß production and degrading levels. Immunofluorescence staining was used to determine the relative integrated density. RESULTS: HT can ameliorate hippocampus-dependent memory deficits and improve synaptic dysfunction by reversing LTP impairment in APP/PS1 transgenic mice. Moreover, HT reduces amyloid plaque deposition by regulating α-secretase and γ-secretase levels. CONCLUSION: HT can improve the learning and memory function of APP/PS1 transgenic mice by improving synaptic function and reducing amyloid plaque deposition.