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1.
Life Sci ; 265: 118844, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33278389

RESUMO

AIMS: Methamphetamine (METH) has become a major public health problem because of its abuse and profound neurotoxic effects, causing alterations in brain structure and function, and impairing cognitive functions, including attention, decision making, emotional memory, and working memory. This study aimed to determine whether melatonin (MEL), the circadian-control hormone, which has roles beyond circadian rhythm regulation, could restore METH-induced cognitive and neuronal impairment. MAIN METHODS: Mice were treated with either METH (1 mg/kg) or saline for 7 days, followed by MEL (10 mg/kg) or saline for another 14 days. The Morris water maze (MWM) test was performed one day after the last saline or MEL injection. The hippocampal neuronal density, synaptic density, and receptors involved in learning and memory, along with downstream signaling molecules (NMDA receptor subunits GluN2A, GluN2B, and CaMKII) were investigated by immunoblotting. KEY FINDINGS: METH administration significantly extended escape latency in learning phase and reduced the number of target crossings in memory test-phase as well as decreased the expression of BDNF, NMDA receptors, TrkB receptors, CaMKII, ßIII tubulin, and synaptophysin. MEL treatment significantly ameliorated METH-induced increased escape latency, decreased the number of target crossings and decreased expression of BDNF, NMDA receptors, TrkB receptors, CaMKII, ßIII tubulin and synaptophysin. SIGNIFICANCE: METH administration impairs learning and memory in mice, and MEL administration restores METH-induced neuronal impairments which is probably through the changes in BDNF, NMDA receptors, TrkB receptors, CaMKII, ßIII tubulin and synaptophysin. Therefore, MEL is potentially an innovative and promising treatment for learning and memory impairment of humans.


Assuntos
Hipocampo/efeitos dos fármacos , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Metanfetamina/toxicidade , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Cognição/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/patologia
2.
Life Sci ; 264: 118660, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127512

RESUMO

AIMS: To evaluate the impact of galangin treatment on cerebral ischemia-reperfusion (I/R) injury in gerbils and to identify potential mechanisms of the protective effect of galangin on hippocampal neurons after I/R injury. PRINCIPAL METHODS: A cerebral ischemia model using bilateral common carotid artery ligation in gerbils was established. The Morris water maze (MWM) test was used to evaluate the learning and memory ability of gerbils. The cell viability was evaluated with an MTT assay. The levels of lipid peroxide biomarkers were measured to estimate the injury due to lipid peroxide. The morphology was detected by electron micrography, immunofluorescence and Nissl staining. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to measure the molecular characteristics. KEY FINDINGS: In the MWM, gerbils treated with galangin after I/R injury showed significant improvements in learning and memory. In addition, galangin treatment reduced the levels of lipid peroxide in the brains of gerbils that underwent I/R as well as reduced the amount of cell death and increased the expression of SLC7A11 and glutathione peroxidase 4 (GPX4). Furthermore, the expression of the marker of ferroptosis was decreased in galangin-treated gerbils, and the effect of galangin was weakened when SLC7A11 was knocked down. These results show that galangin can inhibit ferroptosis by enhancing the expressions of SLC7A11 and GPX4 as well as reduce neuronal cell death. SIGNIFICANCE: Galangin inhibits ferroptosis through activation of the SLC7A11/GPX4 axis and has a protective effect on hippocampal neurons in gerbils after I/R.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Isquemia Encefálica/tratamento farmacológico , Ferroptose , Flavonoides/uso terapêutico , Glutationa Peroxidase/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/fisiopatologia , Ferroptose/efeitos dos fármacos , Flavonoides/farmacologia , Gerbillinae , Hipocampo/patologia , Aprendizagem/efeitos dos fármacos , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
4.
Life Sci ; 263: 118524, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33011218

RESUMO

AIM: Sleep deprivation (SD) is a frequent health problem in modern society. Osthole (Ost), a natural coumarin, has antioxidant and neuroprotective properties. This study examined the functions of Ost in chronic sleep deprivation (CSD)-induced memory deficits in rats. MAIN METHODS: The CSD rat model was constructed by applying Sleep Interruption Apparatus (SIA). The protective effect of Ost on memory ability of CSD rats was evaluated through behavioral tests. Modafinil (MOD) was a positive control for investigating the mechanisms underlying the actions of Ost. The oxidative stress changes in the cortex and hippocampus of the rats, histological changes in CA1 region in the hippocampus and the protein expressions of neural plasticity markers were measured. The hippocampal neurons were isolated from rats for evaluating the neuroprotective effects of Ost on glutamate-induced neuron injury in vitro. KEY FINDINGS: Ost administration significantly enhanced the cognitive performance of CSD rats in the open field test, object location recognition experiment, novel object recognition experiment, and Morris water maze test. Ost could effectively normalize the levels/activities of the antioxidant enzyme system in the cortex and hippocampus. Moreover, Ost administration reversed CSD-induced abnormal state of CA1 neurocytes and the down-regulated expressions of plasticity-related genes in vivo and in vitro. Additionally, Ost also notably up-regulated the expressions of Nrf2 and HO-1 previously down-regulated in CA1 neurocytes of CSD rats and in vitro. SIGNIFICANCE: Our findings showed that Ost alleviated CSD-induced cognitive deficits, and the activation of the Nrf2/HO-1 pathway might be involved in the neuroprotective action of Ost.


Assuntos
Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Cumarínicos/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Privação do Sono/complicações , Animais , Modelos Animais de Doenças , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Ratos , Ratos Wistar
5.
Sci Rep ; 10(1): 16424, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009465

RESUMO

Trigonelline (TGN; 1-methylpyridin-1-ium-3-carboxylate) is a widely distributed alkaloid derived from plants. Since we previously found a neurite outgrowth effect of TGN, we hypothesised that TGN might help to improve memory deficits. Here, the efficacy of TGN in restoring amyloid ß (Aß)-induced axonal degeneration and in improving memory function was investigated in Alzheimer's disease 5XFAD model mice that overexpress mutated APP and PS1 genes. Exposure of Aß25-35 for 3 days induced atrophy of axons and dendrites. Post treatment of TGN recovered the lengths of axons and dendrites. Following oral administration of TGN in mice, TGN itself was detected in the plasma and cerebral cortex. Oral administration of TGN to 5XFAD mice for 14 days showed significant improvement in object recognition memory (P < 0.001) and object location memory (P < 0.01). TGN administration also normalised neurofilament light levels in the cerebral cortex (P < 0.05), which is an axonal damage-associated biomarker. Analysis of target proteins of TGN in neurons by a drug affinity responsive target stability (DARTS) method identified that creatine kinase B-type (CKB) is a direct binding protein of TGN. Treatment with a CKB inhibitor cancelled the TGN-induced axonal and dendritic growth. In conclusion, we found for the first time that TGN penetrates the brain and may activate CKB, leading to axonal formation. This study shows the potential of TGN as a new drug candidate, and a new target molecule, CKB, in memory recovery signalling.


Assuntos
Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Córtex Cerebral/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Alcaloides/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Atrofia/tratamento farmacológico , Atrofia/metabolismo , Axônios/efeitos dos fármacos , Axônios/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo
6.
Phytomedicine ; 79: 153320, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920285

RESUMO

BACKGROUND: Neurodegenerative diseases (NDDs) are primarily characterized by selective neuronal loss in the brain. Alzheimer's disease as the most common NDDs and the most prevalent cause of dementia is characterized by Amyloid-beta deposition, which leads to cognitive and memory impairment. Parkinson's disease is a progressive neurodegenerative disease characterized by the dramatic death of dopaminergic neuronal cells, especially in the SNc and caused alpha-synuclein accumulation in the neurons. Silymarin, an extract from seeds of Silybum marianum, administered mostly for liver disorders and also had anti-oxidant and anti-carcinogenic activities. PURPOSE: The present comprehensive review summarizes the beneficial effects of Silymarin in-vivo and in-vitro and even in animal models for these NDDs. METHODS: A diagram model for systematic review is utilized for this search. The research is conducted in the following databases: PubMed, Web of Science, Scopus, and Science Direct. RESULTS: Based on the inclusion criteria, 83 studies were selected and discussed in this review. CONCLUSION: Lastly, we review the latest experimental evidences supporting the potential effects of Silymarin, as a neuroprotective agent in NDDs.


Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Silimarina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Transtornos da Memória/tratamento farmacológico , Cardo-Mariano/química , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico
7.
Phytomedicine ; 79: 153338, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32992081

RESUMO

BACKGROUND: Pu'er tea, a type of post-fermented tea made from Camellia sinensis leaves, has long been widely used in East Asian countries. It is mainly produced in southern China and is effective in preventing obesity due to its ability to break down fat. However, the effects of Pu'er tea on cognitive impairment or neuroinflammation by endotoxin have not yet been studied. PURPOSE: Here, we assessed the inhibitory activity of Pu'er tea hot water extract (PTW) on neuroinflammation and cognitive impairment and explored its mechanism. STUDY DESIGN: The ability of PTW to inhibit cognitive impairment was investigated in a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation and murine microglia BV2 cells. METHODS: We examined whether oral administration of PTW prevented cognitive impairment and LPS-induced neuroinflammation using behavioral tests, Nissl staining, immunohistochemistry, western blotting, real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), Griess assay, and enzyme-linked immunosorbent assay (ELISA). RESULTS: First, Morris water maze (MWM) and passive avoidance (PA) tests demonstrated that oral administration of PTW effectively attenuated LPS-induced spatial memory loss and inhibited neuronal damage of mouse brains. Histopathological analysis showed that PTW repressed LPS-induced expression of the activation markers ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP). Furthermore, PTW inhibited the expression of amyloidogenesis proteins such as amyloid-ß precursor protein (APP), C99, and ß-secretase-1 (BACE-1); production of inflammatory proteins such as Iba-1, GFAP, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2; activation of inflammatory pathways; and expression of inflammatory mediator mRNAs in hippocampal tissue. In cultured microglia, PTW treatment inhibited the generation of various inflammatory factors activated by LPS. CONCLUSION: Our results in vivo and in vitro demonstrate that PTW effectively prevents cognitive impairment caused by neuroinflammation and is, therefore, a potential candidate for the development of a therapeutic agent for neurodegenerative diseases.


Assuntos
Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Alimentos e Bebidas Fermentados , Chá , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/patologia , Células Cultivadas , Disfunção Cognitiva/induzido quimicamente , Modelos Animais de Doenças , Alimentos e Bebidas Fermentados/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Microglia/patologia , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Chá/química
8.
Nat Commun ; 11(1): 4790, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963242

RESUMO

Preventing aggregation of amyloid beta (Aß) peptides is a promising strategy for the treatment of Alzheimer's disease (AD), and gold nanoparticles have previously been explored as a potential anti-Aß therapeutics. Here we design and prepare 3.3 nm L- and D-glutathione stabilized gold nanoparticles (denoted as L3.3 and D3.3, respectively). Both chiral nanoparticles are able to inhibit aggregation of Aß42 and cross the blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses a larger binding affinity to Aß42 and higher brain biodistribution compared with its enantiomer L3.3, giving rise to stronger inhibition of Aß42 fibrillation and better rescue of behavioral impairments in AD model mice. This conjugation of a small nanoparticle with chiral recognition moiety provides a potential therapeutic approach for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Ouro/farmacologia , Transtornos da Memória/tratamento farmacológico , Nanopartículas Metálicas/química , Fragmentos de Peptídeos/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/metabolismo , Estereoisomerismo
9.
Planta Med ; 86(18): 1389-1399, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32797467

RESUMO

Alzheimer's disease, one of the most common types of age-related dementia, is characterized by memory deterioration and behavior disorder. The aboveground part of Polygala tenuifolia is a traditional Chinese medicine used for the treatment of amnesia. This study was conducted to investigate the ameliorating effect of the aerial part of P. tenuifolia on d-galactose/NaNO2-induced learning and memory impairment in mice. d-galactose (120 mg/kg) and NaNO2 (90 mg/kg) were injected intraperitoneally for 60 days to induce learning and memory impairment in mice. The aerial part of P. tenuifolia (25, 50, and 100 mg/kg) and piracetam (200 mg/kg) were simultaneously administered orally on days 15 - 60. Results of this study showed that aerial part of P. tenuifolia significantly decreased the latency time and increased the number of platform crossings in the Morris water maze compared with the Model group. Moreover, the aerial part of P. tenuifolia significantly increased the latency time and decreased the error frequency in the step-down and step-through tests compared with the Model group. Meanwhile, the aerial part of P. tenuifolia was able to regulate the cholinergic system by increasing the levels of ACh and ChAT and decreasing the level of AChe. The aerial part of P. tenuifolia also significantly attenuated the levels of interleukin-1 beta and malonaldehyde and enhanced the interleukin-10 and glutathione levels and superoxide dismutase activity. Furthermore, treatment with aerial part of P. tenuifolia increased the protein and mRNA expression of brain-derived neurotrophic factor and tropomyosin receptor kinase B in the hippocampus. These results suggest that the aerial part of P. tenuifolia can ameliorate learning and memory impairments by modulating cholinergic activity, inhibiting neuroinflammation and oxidative stress, and regulating the brain-derived neurotrophic factor and tropomyosin receptor kinase B signaling pathway.


Assuntos
Polygala , Animais , Galactose , Hipocampo , Aprendizagem em Labirinto , Memória , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Componentes Aéreos da Planta , Extratos Vegetais/farmacologia
10.
Life Sci ; 260: 118338, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841662

RESUMO

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Inibidores de Captação de Serotonina/farmacologia
11.
Sci Rep ; 10(1): 8944, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488040

RESUMO

Oxidative stress due to hypobaric hypoxia at extreme altitudes causes severe neuronal damage and irreversible cognitive loss. Owing to contraindications of current drug therapies, the aim of the study was to investigate memory enhancing potential of aqueous extract of Ganoderma lucidum (GLAQ) and underlying neuroprotective mechanism using rat hypobaric hypoxia test model. Rats exposed to hypobaric hypoxia showed deranged spatial memory in morris water maze test with hippocampal damage and vasogenic cerebral edema. All these changes were prevented with GLAQ treatment. Blood and biochemical analysis revealed activation of hypoxic ventilatory response, red blood cells induction, reversal of electrolyte and redox imbalance, and restoration of cellular bioenergetic losses in GLAQ treated animals. Notably, GLAQ treatment ameliorated levels of neurotransmitters (catecholamines, serotonin, glutamate), prevented glucocorticoid and α-synuclein surge, improved neuroplasticity by upregulating CREB/p-CREB/BDNF expression via ERK1/ERK2 induction. Further, restoration of nuclear factor erythroid 2-related factor with stabilization of hypoxia inducible factors and inflammatory markers were evidenced in GLAQ treated rats which was additionally established in gene reporter array using an alternative HT22 cell test model. Conclusively, our studies provide novel insights into systemic to molecular level protective mechanism by GLAQ in combating hypobaric hypoxia induced oxidative stress and memory impairment.


Assuntos
Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacologia , Reishi/metabolismo , Animais , Encéfalo/metabolismo , Hipocampo/metabolismo , Homeostase , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transmissão Sináptica/efeitos dos fármacos
13.
Int J Med Mushrooms ; 22(2): 145-159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479003

RESUMO

One of the major causes of Alzheimer's disease (AD) is oxidative stress, which accelerates ß-amyloid peptide (AP) plaque and neurofibrillary tangle accumulation in the brain. Pleurotus eryngii is known to be rich in antioxidants, including ergothioneine, adenosine, and polyphenol, which can reduce oxidative stress-related aging. The aim of this study was to investigate the proximate and functional composition of P. eryngii, and evaluate the cognitive effects of low (LPE), medium (MPE), and high (HPE) P. eryngii dosages in an Aß-induced Alzheimer's disease C57BL/6J mouse model. Mice fed P. eryngii for six weeks showed no adverse effects on body weight gain, food intake efficiency, serum biochemical parameters, and liver and kidney histopathological features. The relative brain weight was significantly lower in Aß-injected mice (p < 0.05). Further, P. eryngii was shown to delay brain atrophy. Reference memory behavioral tasks showed that LPE, MPE, and HPE significantly decreased escape latency (49-85%) and distance (53-69%, p < 0.05). Probe and T-maze tasks showed that P. eryngii potently ameliorated memory deficit in mice. An AD pathology index analysis showed that P. eryngii significantly decreased levels of brain phosphorylated τ-protein, Aß plaque deposition, malondialdehyde, and protein carbonyl (p < 0.05). P. eryngii may therefore promote memory and learning capacity in an Aß-induced AD mouse model.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Carpóforos/química , Deficiências da Aprendizagem/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Pleurotus/química , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/efeitos adversos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antioxidantes/química , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Deficiências da Aprendizagem/patologia , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Pós/química , Pós/farmacologia
14.
J Pharmacol Sci ; 143(4): 245-254, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32482409

RESUMO

The accumulation of insoluble amyloid ß (Aß) peptides is one of the pathological changes in Alzheimer's disease (AD), which induced synaptic plasticity impairment and excitatory amino acid toxicity associated with decreased memory function. Xingnaojing (XNJ), a well-known prescription in traditional Chinese medicine, has been used for the treatment of stroke for many years in China. In this study, we aim to investigate the therapeutic effects of XNJ in a hippocampus of Aß1-42 induced mouse model of AD which showed significant memory loss and impaired synaptic morphology and function. Treatment of XNJ could attenuate spatial and working memory dysfunction, increase dendritic spine density and improve long-term potential (LTP) induction. In addition, XNJ treatment significantly increased the level of N-methyl-d-aspartate receptors (NMDARs) and inhibit the NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) ratio in AD mice. XNJ treatment also activated the AKT/mechanistic target of rapamycin (mTOR) pathway, while inhibition of the mTOR pathway by rapamycin could reverse the protective effects of XNJ treatment. In conclusion, XNJ protected against synaptic plasticity and memory impairment in AD mice via the activation of AKT/mTOR signaling pathway, suggesting XNJ as an alternative treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL
15.
Life Sci ; 255: 117861, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32473247

RESUMO

Alzheimer's disease (AD) is closely associated with neuroinflammation development in the brain. Co-delivery of metformin (MET) with phosphatidylserine liposomes neuroprotectant may be beneficial in ameliorating AD-related symptoms like memory impairment and inflammation. Therefore, we aimed to prepare metformin containing phosphatidylserine nanoliposomes formulation (MET-PSL) and to evaluate its effect on rats subjected to AD. Alzheimer's disease model was induced by bilateral intracerebroventricular injection of streptozotocin (3 mg/kg) into rat brains using the stereotactic technique. MET-PSL, MET, and PSL alone were administered intraperitoneally to AD-induced animals and factors including learning and memory storage in addition to cytokine and tissue inflammatory changes were evaluated after a 22-day experiment period. The learning and memory parameters significantly (P < 0.05) improved in AD-rats treated with MET-PSL. Moreover, MET-PSL administration significantly (P < 0.05) decreased cytokine levels of IL1-ß, TNF-α, and TGF-ß in hippocampal tissues of rats with AD. Histological results indicated a considerable reduction in inflammatory and necrotic neural cells along with significantly (P < 0.05) increased neurogenesis in MET-PSL treated rats. Furthermore, our results showed that MET-PSL formulation could potentially act better than the free form of MET and PSL alone in the recovery process of rats with AD. In general, our data suggest that combination therapy of metformin loaded phosphatidylserine liposomes may enhance the therapeutic performance in AD patients of a clinical study.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Metformina/farmacologia , Nanopartículas , Fosfatidilserinas/química , Doença de Alzheimer/fisiopatologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Lipossomos , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/fisiopatologia , Ratos , Ratos Wistar , Estreptozocina
16.
Chem Biol Interact ; 326: 109113, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360496

RESUMO

Apple polyphenols (AP) have attracted much attention due to their various bioactivities. In this study, the protective effect of AP against chronic ethanol exposure-induced neural injury as well as the possible mechanisms were investigated. Body weight, daily average food intake and daily average fluid intake were measured and daily average ethanol consumption was calculated. The influences of AP on motor behavior and memory were detected by locomotor activity test, rotarod test, beam walking test, and Y maze test and novel object recognition test, respectively. The changes of blood ethanol concentration and the oxidative stress were also measured. AP improved chronic ethanol exposure-induced the inhibition of body weight and the decrease of daily average food intake, but did not influence the daily average fluid intake and the daily average ethanol intake, indicating that the improve effect of AP did not result from the decrease of ethanol intake. Motor activity and motor coordination were not influenced after chronic ethanol exposure though the blood ethanol concentration was higher than that in control group. AP improved significantly chronic ethanol-induced the memory impairment and the hippocampal CA1 neurons damage. Further studies found that AP decreased the contents of NO and MDA and increased the levels of T-AOC and GSH in the hippocampus of rats. These results suggest that AP exerts a protective effect against chronic ethanol-induced memory impairment through improving the oxidative stress in the hippocampus.


Assuntos
Etanol/efeitos adversos , Neurônios/efeitos dos fármacos , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Animais , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Malus , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Cell Physiol Biochem ; 54(3): 438-456, 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32357291

RESUMO

BACKGROUND/AIMS: Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D9k (CaBP-9k) acts as calcium modulators and sensors in various tissues. However, the neurobiological functions of CaBP-9k are unknown. METHODS: We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice. RESULTS: We found that the brains of CaBP-9k KO mice have increased APP/ß-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice. CONCLUSION: Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.


Assuntos
Doença de Alzheimer/genética , Apoptose/genética , Calbindinas/genética , Estresse do Retículo Endoplasmático/genética , Doença de Parkinson/genética , Ácido Tauroquenodesoxicólico/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Calbindinas/metabolismo , Cálcio/metabolismo , Proliferação de Células/genética , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , RNA Interferente Pequeno , Fatores de Risco , Ácido Tauroquenodesoxicólico/farmacologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
18.
PLoS One ; 15(5): e0233468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469975

RESUMO

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Transtornos da Memória/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Oxidiazóis/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Epigênese Genética/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacocinética , Oxidiazóis/química , Oxidiazóis/farmacocinética , Ratos , Ratos Sprague-Dawley
19.
Molecules ; 25(7)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32230815

RESUMO

The present study investigated the capability of an essential oil mix (MO: 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP: 5 mg/kg) was used as a positive reference drug. The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography-mass spectrometry (GC-MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), ß-myrcene (1.92%), ß-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status.


Assuntos
Amnésia/tratamento farmacológico , Antioxidantes/farmacologia , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Óleos Voláteis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Escopolamina/efeitos adversos , Acetilcolinesterase/metabolismo , Amnésia/induzido quimicamente , Animais , Escala de Avaliação Comportamental , Encéfalo/enzimologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Donepezila/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Limoneno/farmacologia , Limoneno/uso terapêutico , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Simulação de Acoplamento Molecular , Óleos Voláteis/análise , Óleos Voláteis/uso terapêutico , Ratos , Ratos Wistar
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