RESUMO
To investigate the therapeutic efficacy of Scutellarin (SCU) on neurite growth and neurological functional recovery in neonatal hypoxic-ischemic (HI) rats. Primary cortical neurons were cultured to detect the effect of SCU on cell viability of neurons under oxygen-glucose deprivation (OGD). Double immunofluorescence staining of Tuj1 and TUNEL then observed the neurite growth and cell apoptosis in vitro,and double immunofluorescence staining of NEUN and TUNEL was performed to examine the neuronal apoptosis and cell apoptosis in brain tissues after HI in vivo. Pharmacological efficacy of SCU was also evaluated in HI rats by neurobehavioral tests, triphenyl tetrazolium chloride staining, Hematoxylin and eosin staining and Nissl staining. Astrocytes and microglia expression in damaged brain tissues were detected by immunostaining of GFAP and Iba1. A quantitative real-time polymerase chain reaction and western blot were applied to investigate the genetic expression changes and the protein levels of autophagy-related proteins in the injured cortex and hippocampus after HI. We found that SCU administration preserved cell viability, promoted neurite outgrowth and suppressed apoptosis of neurons subjected to OGD both in vitroand in vivo. Meanwhile, 20 mg/kg SCU treatment improved neurological functions and decreased the expression of astrocytes and microglia in the cortex and hippocampus of HI rats. Additionally, SCU treatment depressed the elevated levels of autophagy-related proteins and the p75 neurotrophin receptor (p75NTR) in both cortex and hippocampus. This study demonstrated the potential therapeutic efficacy of SCU by enhancing neurogenesis and restoring long-term neurological dysfunctions, which might be associated with p75NTR depletion in HI rats.
Assuntos
Animais Recém-Nascidos , Apigenina/farmacologia , Apigenina/uso terapêutico , Encéfalo/fisiopatologia , Glucuronatos/farmacologia , Glucuronatos/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/genética , Neurogênese/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Encéfalo/citologia , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Ratos , Receptores de Fatores de Crescimento/metabolismoRESUMO
Music exposure is known to play a positive role in learning and memory and can be a complementary treatment for anxiety and fear. However, whether juvenile music exposure affects adult behavior is not known. Two-week-old Sprague-Dawley rats were exposed to music for 2 hours daily or to background noise (controls) for a period of 3 weeks. At 60 days of age, rats were subjected to auditory fear conditioning, fear extinction training, and anxiety-like behavior assessments or to anterior cingulate cortex (ACC) brain-derived neurotrophic factor (BDNF) assays. We found that the music-exposed rats showed significantly less freezing behaviors during fear extinction training and spent more time in the open arm of the elevated plus maze after fear conditioning when compared with the control rats. Moreover, the BDNF levels in the ACC in the music group were significantly higher than those of the controls with the fear conditioning session. This result suggests that music exposure in juvenile rats decreases anxiety-like behaviors, facilitates fear extinction, and increases BDNF levels in the ACC in adulthood after a stressful event.
Assuntos
Ansiedade/terapia , Musicoterapia , Música , Transtornos Fóbicos/terapia , Animais , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Medo/fisiologia , Humanos , Memória/fisiologia , Transtornos Fóbicos/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
Mature brain-derived neurotrophic factor (mBDNF) has neuroprotection in cerebral ischemia. Conversely, the precursor of brain-derived neurotrophic factor (proBDNF) has the opposite function to its mature form, inducing apoptosis. However, whether the neuroprotection of Panax notoginsenoside Rb1 (PNS-Rb1) on ischemic stroke is due to, at least partially, its modulation of suppressing proBDNF/P75NTR/sortilin or upregulation of mBDNF is not clear. To test this hypothesis, rats induced by photothrombotic stroke were treated with PNS-Rb1 100 mg/kg or nimodipine 1 mg/kg twice a day until 3, 7, and 14 days. Our data indicate that PNS-Rb1 significantly reduced cerebral infarction rate, proBDNF/P75NTR/sortilin, and plasminogen activator inhibitor-1 (PAI-1) protein levels, and improved sensorimotor dysfunctions induced by ischemic stroke, upregulation of BDNF/TrkB levels, and its processing enzymes (tissue plasminogen activator, tPA) in a time-dependent manner. Taken together, our findings indicate that the improvement of sensorimotor dysfunctions by PNS-Rb1 following ischemic stroke is made, at least partially, by activating the BDNF/TrkB and inhibiting proBDNF/sortilin/P75NTR.
Assuntos
Fármacos Neuroprotetores/uso terapêutico , Saponinas/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Western Blotting , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Masculino , Destreza Motora , Proteínas do Tecido Nervoso , Panax , Precursores de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/metabolismo , Acidente Vascular Cerebral/metabolismoRESUMO
Panax notoginsenoside saponins Rb1 (PNS-Rb1) is an important active ingredient of panax notoginseng for effective treatment of cerebrovascular diseases. However, the mechanism underlying its actions in the state of cerebral ischemia is still unclear. We asked whether the potential neuroprotection of PNS-Rb1 on the brain is due to, at least partially, its modulation of AkT/mTOR/PTEN signalling pathway along with down-regulation of caspase-3 in rats subjected to phototrombic stroke. To test this hypothesis, rats with induced photothrombotic stroke were treated with PNS-Rb1 (applied in three different doses, 25â¯mg/kg, 50â¯mg/kg,100â¯mg/kg, respectively) or saline, while sham operated rats injected with saline were used as the control. Our results indicate that PNS-Rb1 significantly alleviated the morphological lesion concomitant with improvement of cognitive and sensorimotor deficits induced by ischemic stroke. Moreover, immunohistochemistry and Western blot analyses showed that PNS Rb1 in a dose dependent manner increased the expressions of P-Akt, P-mTOR and reduced P-PTEN and caspase-3. The present study suggests that the improvement of cognitive and sensorimotor deficits by PNS-Rb1 is made, at least partially, by the modulation of the Akt/mTOR/PTEN signalling pathway.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Saponinas/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/psicologia , Caspase 3/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Fármacos Neuroprotetores/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Panax notoginseng , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/psicologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Accumulated evidence suggests that polyphenolic antioxidants present in herbs play important roles in prevention of AD; the molecular mechanisms behind neuroprotective actions rely on the phenols through different effects on the amyloid-aggregation pathway. Fagopyrum dibotrys is a traditional herbal medicine which contains high quantity phenols. In present study, we investigate the beneficial pharmacological actions of Fagopyrum dibotrys extract in the APP/PS1 transgenic mouse mode; meanwhile, effects of the FDE on the fibrillation and cytotoxicity of Aß peptide were evaluated in vitro. After 9-month treatment, FDE exhibited multifunctional properties on Aß-related pathologies, which cleaned Aß deposits in the brain and decreased Aß burden in the plasma, inhibited microhaemorrhage, and reduced reactive microglia in APP/PS1 transgenic mice and also promoted Aß fibrils disaggregation and inhibited neurotoxicity induced by Aß in SH-SY5Y cells. These results highlighted that FDE is an AD type pathology modulator with therapeutic potential against AD.
RESUMO
Cerebral ischemia damages central neurons, and abnormal microenvironment in ischemic condition is the key factor to the damages. The increase of local concentration of glutamic acid, the overload of Ca2+, and the mitochondrial stress caused by release of cytochrome C are important factors of abnormal microenvironment in cerebral ischemia. In this study ginsenoside Rb1, a compound from Panax Notoginseng, was used to intervene abnormal environment of neurons in the hippocampal CA1 region in two animal models (microperfusion model and photothrombosis model). RESULTS: Compared with the vehicle in the sham group, ginsenoside had following effects. a) ginsenoside Rb1 increased the regional cerebral blood flow (rCBF) and the stability of neuronal ultrastructure in in the hippocampal CA1 region and improved the adaptability of neurons in two models. b) ginsenoside Rb1 improved the expression level of glial glutamate transporter1 (GLT-1) and reversed the uptake of glutamate (Glu) after ischemia, and as a result thereby decreased the excitability of Glu and the expression level of GLT-1 was proportional to the dose of ginsenoside Rb1 and similar to that of Nimodipine. c) ginsenoside Rb1 inhibited the expression level of NMDAR and the overload of Ca2+, thereby reducing neuronal damages. Meanwhile, the expression level of NMDAR was inversely proportional to the dose of ginsenoside Rb1, which was similar to that of Nimodipine. d) ginsenoside Rb1 decreased the release of cytochrome C (Cyt-C) and reduced the damages caused by neuronal mitochondrial stress. Meanwhile, the release of Cyt-C was inversely proportional to the dose of ginsenoside Rb1, which was similar to that of Nimodipine. Ginsenoside Rb1 may be as an effective drug for neuroprotection and improve cerebral blood flow after acute ischemia and prevent the secondary brain damage induced by stroke.
Assuntos
Microambiente Celular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Citocromos c/metabolismo , Transportador 2 de Aminoácido Excitatório/biossíntese , Transportador 2 de Aminoácido Excitatório/genética , Ácido Glutâmico/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Nimodipina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Defective neurogenesis in the postnatal brain can lead to many neurological and psychiatric disorders, yet the mechanism behind postnatal neurogenesis remains to be investigated. Huntingtin-associated protein 1 (HAP1) participates in intracellular trafficking in neurons, and its absence leads to postnatal death in mice. Here, we used tamoxifen-induced (TM-induced) Cre recombination to deplete HAP1 in mice at different ages. We found that HAP1 reduction selectively affects survival and growth of postnatal mice, but not adults. Neurogenesis, but not gliogenesis, was affected in HAP1-null neurospheres and mouse brain. In the absence of HAP1, postnatal hypothalamic neurons exhibited reduced receptor tropomyosin-related kinase B (TRKB) levels and decreased survival. HAP1 stabilized the association of TRKB with the intracellular sorting protein sortilin, prevented TRKB degradation, and promoted its anterograde transport. Our findings indicate that intracellular sorting of neurotrophin receptors is critical for postnatal neurogenesis and could provide a therapeutic target for defective postnatal neurogenesis.
Assuntos
Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Receptor trkB/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Hipotálamo/citologia , Hipotálamo/metabolismo , Sistema Límbico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/fisiologia , Especificidade de Órgãos , Estabilidade Proteica , Transporte Proteico , Proteólise , Esferoides Celulares/fisiologiaRESUMO
Polyphenols extracted from grape seeds are able to inhibit amyloid-beta (Abeta) aggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We aimed to investigate the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in Alzheimer's disease (AD) mice. APP(Swe)/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid (49 mg/g), catechin (41 mg/g), epicatechin (66 mg/g) and proanthocyanidins (436.6 mg catechin equivalents/g). Long-term feeding of GSE diet was well tolerated without fatality, behavioural abnormality, changes in food consumption, body weight or liver function. The Abeta levels in the brain and serum of the mice fed with GSE were reduced by 33% and 44%, respectively, compared with the Alzheimer's mice fed with the control diet. Amyloid plaques and microgliosis in the brain of Alzheimer's mice fed with GSE were also reduced by 49% and 70%, respectively. Curcumin also significantly reduced brain Abeta burden and microglia activation. Conclusively, polyphenol-rich GSE prevents the Abeta deposition and attenuates the inflammation in the brain of a transgenic mouse model, and this thus is promising in delaying development of AD.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encefalite/etiologia , Extrato de Sementes de Uva/farmacologia , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Citocinas/sangue , Dietoterapia/métodos , Modelos Animais de Doenças , Encefalite/dietoterapia , Encefalite/patologia , Ensaio de Imunoadsorção Enzimática , Flavonoides/farmacologia , Extrato de Sementes de Uva/química , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/sangue , Fenóis/farmacologia , Polifenóis , Presenilina-1/genéticaRESUMO
The study set out to determine (a) whether DNA damage is elevated in mice that carry mutations in the amyloid precursor protein (APP695swe) and presenilin 1 (PSEN1-dE9) that predispose to Alzheimer's disease (AD) relative to non-transgenic control mice, and (b) whether increasing the intake of dietary polyphenols from curcumin or grape seed extract could reduce genomic instability events in a transgenic mouse model for AD. DNA damage was measured using the micronucleus (MN) assay in both buccal mucosa and erythrocytes and an absolute telomere length assay for both buccal mucosa and olfactory bulb tissue. MN frequency tended to be higher in AD mice in both buccal mucosa (1.7-fold) and polychromatic erythrocytes (1.3-fold) relative to controls. Telomere length was significantly reduced by 91% (p=0.04) and non-significantly reduced by 50% in buccal mucosa and olfactory bulbs respectively in AD mice relative to controls. A significant 10-fold decrease in buccal MN frequency (p=0.01) was found for AD mice fed diets containing curcumin (CUR) or micro-encapsulated grape seed extract (MGSE) and a 7-fold decrease (p=0.02) for AD mice fed unencapsulated grape seed extract (GSE) compared to the AD group on control diet. Similarly, in polychromatic erythrocytes a significant reduction in MN frequency was found for the MGSE cohort (65.3%) (p<0.05), whereas the AD CUR and AD GSE groups were non-significantly reduced by 39.2 and 34.8% respectively compared to the AD Control. A non-significant 2-fold increase in buccal cell telomere length was evident for the CUR, GSE and MGSE groups compared to the AD control group. Olfactory bulb telomere length was found to be non-significantly 2-fold longer in mice fed on the CUR diet compared to controls. These results suggest potential protective effects of polyphenols against genomic instability events in different somatic tissues of a transgenic mouse model for AD.