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1.
PLoS One ; 15(7): e0235979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706773

RESUMO

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidß in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid ßby trapping amyloid ß onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/administração & dosagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Transtornos da Memória/prevenção & controle , Nanofibras/administração & dosagem , Placa Amiloide/prevenção & controle , Administração Intranasal , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Feminino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanofibras/química , Placa Amiloide/etiologia , Placa Amiloide/patologia
2.
Eur J Med Chem ; 200: 112405, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32492595

RESUMO

A series of 4-phenyl-6H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylate esters were synthesized and tested as central benzodiazepine receptor (CBR) ligands by the ability to displace [3H]flumazenil from rat cortical membranes. All the compounds showed high affinity with IC50 values ranging from 5.19 to 16.22 nM. In particular, compounds 12b (IC50 = 8.66 nM) and 12d (IC50 = 5.19 nM) appeared as the most effective ligands being their affinity values significantly lower than that of diazepam (IC50 = 18.52 nM). Compounds 12a-f were examined in vivo for their pharmacological effects in mice and five potential benzodiazepine (BDZ) actions were thus taken into consideration: anxiolytic, anticonvulsant, anti-amnesic, hypnotic, and locomotor activities. All the new synthesized compounds were able to induce a significant antianxiety effect and, among them, compound 12f protected pentylenetetrazole (PTZ)-induced convulsions in a dose-dependent manner reaching a 40% effect at 30 mg/kg. In addition, all the compounds were able to significantly prevent the memory impairment evoked by scopolamine, while none of them was able to interfere with pentobarbital-evoked sleep and influence motor coordination. Moreover, title compounds did not affect locomotor and exploratory activity at the same time and doses at which the anti-anxiety effect was observed. Finally, molecular docking simulations were carried out in order to assess the binding mode for compounds 12a-f. The obtained results demonstrated that these compounds bind the BDZ binding site in a similar fashion to flumazenil.


Assuntos
Ansiolíticos/síntese química , Benzodiazepinas/química , Desenho de Fármacos , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes , Benzodiazepinas/metabolismo , Sítios de Ligação , Locomoção/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Camundongos , Simulação de Acoplamento Molecular , Ratos , Receptores de GABA-A/metabolismo
3.
PLoS One ; 15(4): e0231578, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298362

RESUMO

BACKGROUND: Adherence to treatment is a crucial factor for patients who have chronic illnesses or multiple morbidities and polypharmacy, which is frequently found in older adults. The non-adherence to medications has important economic and social consequences as well as impacts on the health of the patients. One of the reasons that can explain the low adherence to treatment, is the memory deficits that are characteristics of this population and that are even more evident in cases that involve neurodegenerative diseases. METHODS AND FINDINGS: In this study, we explore whether the differential outcomes procedure (DOP), which has been shown to be useful in improving discriminative learning and memory in different populations, may facilitate learning and retention of medical recommendations in older adults who have been diagnosed with Alzheimer's disease. The results demonstrate that when this procedure was applied, the patients showed improvements in learning and long-term retention of two pill/time of day associations in a situation that simulates adherence to medical prescriptions. CONCLUSIONS: These findings contribute new data about the potential benefits of the DOP in patients with neurodegenerative disorders, highlighting the important role that this procedure could play in addressing important issues related to the health and quality of life of older adults, with or without neurodegenerative diseases, such as low adherence to medical treatments.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aprendizagem por Discriminação , Adesão à Medicação , Memória , Idoso , Idoso de 80 Anos ou mais , Aprendizagem por Discriminação/efeitos dos fármacos , Feminino , Humanos , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Pessoa de Meia-Idade , Qualidade de Vida
4.
Life Sci ; 253: 117703, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334010

RESUMO

AIMS: Vitamin D is a well-known endocrine regulator of calcium/phosphate homeostasis and has been reported as having a wide range of activities that are potentially beneficial for human health. This study aimed to investigate the effects of pretreatment of vitamin D3 (100, 1000, and 10,000 IU/kg) against lipopolysaccharide (LPS)-induced cognitive impairment in rats. MAIN METHODS: Male Wistar rats were divided into five groups. The passive avoidance test and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), total thiol content as well as interleukin (IL)-6 were evaluated in the hippocampus tissue. KEY FINDINGS: The intraperitoneal (i.p.) injection of LPS (1 mg/kg) correlates with deficits in passive avoidance and spatial learning in the systemic inflammation model. However, pretreatment with vitamin D3 improved LPS-induced cognitive impairment. In addition, vitamin D3 decreased IL-6 and MDA levels, whereas the activities of CAT, SOD, and total thiol content in the hippocampus tissue were significantly increased. SIGNIFICANCE: In conclusion, our results suggest that vitamin D3 plays a protective role against memory dysfunction caused by LPS-induced inflammation through inhibition of oxidative stress and inflammation in the hippocampus. Vitamin D may be a promising potential therapeutic supplement for the treatment or prevention of learning and memory disorders.


Assuntos
Colecalciferol/farmacologia , Disfunção Cognitiva/prevenção & controle , Inflamação/prevenção & controle , Transtornos da Memória/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Colecalciferol/administração & dosagem , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Lipopolissacarídeos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar
5.
Toxicol Appl Pharmacol ; 395: 114980, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234516

RESUMO

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.


Assuntos
Anti-Inflamatórios/administração & dosagem , Transtornos da Memória/prevenção & controle , Minociclina/administração & dosagem , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Tolueno/toxicidade , Administração por Inalação , Animais , Expressão Gênica/efeitos dos fármacos , Abuso de Inalantes , Interleucina-1beta/genética , Masculino , Transtornos da Memória/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tolueno/administração & dosagem , Fator de Crescimento Transformador beta/genética
6.
J Med Food ; 23(5): 476-484, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32267780

RESUMO

Post-traumatic stress disorder (PTSD) is a stress-associated mental disorder characterized by an imbalance of neurotransmitters in response to traumatic events or fear. Genistein (GEN), a natural isoflavone, has been shown to exhibit neuroprotective effects. Here, we used the Morris water maze (MWM) and object recognition task (ORT) tests to examine the effects of GEN on cognitive impairment in rats after exposure to single prolonged stress (SPS), and its interaction with the serotonergic system. After exposure to SPS, male rats received GEN (2, 4, and 10 mg/kg, i.p.) for 14 days. Daily GEN administration significantly improved cognitive function in the ORT and MWM tests. GEN treatment also inhibited SPS-induced decreases in serotonin (5-HT) levels in the medial prefrontal cortex and hippocampus. These increased 5-HT concentrations in response to GEN treatment could be partially attributed to the ratio of 5-hydroxyindoleacetic acid/5-HT in the hippocampus. Our findings suggest that GEN significantly attenuates SPS-induced memory deficits in rats and may represent an effective therapeutic option for the treatment of PTSD.


Assuntos
Disfunção Cognitiva/prevenção & controle , Genisteína/uso terapêutico , Transtornos da Memória/prevenção & controle , Serotonina/sangue , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Cognição/efeitos dos fármacos , Corticosterona/sangue , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico
7.
Medicina (Kaunas) ; 56(3)2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32183249

RESUMO

In this paper we introduce a mechanistic model through which exercise may enhance episodic memory, specifically via attenuating proactive and retroactive memory interference. We discuss the various types of memory, different stages of memory function, review the mechanisms behind forgetting, and the mechanistic role of exercise in facilitating pattern separation (to attenuate memory interference).


Assuntos
Exercício Físico/fisiologia , Transtornos da Memória/prevenção & controle , Cognição/fisiologia , Humanos , Aprendizagem/fisiologia , Transtornos da Memória/psicologia
8.
Environ Toxicol ; 35(5): 570-581, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31889399

RESUMO

Hypertension (HTN) is one of the most prevalent chronic conditions; it can damage blood vessels and rupture blood vessels can trap in small vessels. This blockage can prevent blood flow and oxygen delivery to brain cells and can result in Alzheimer's disease (AD). HTN- and AD-mediated long-time memory loss and its treatment remain poorly understood. Plant-derived natural compounds are alternative solutions for effectively treating diseases without any side effects. This study revealed that bioactive peptides extracted from potato hydrolysis suppress HTN-mediated long-term memory (LTM) loss and cell apoptosis, thus improving memory formation and neuronal cell survival in the spontaneously hypertensive rat (SHR) rat model. SHR rats were treated with bioactive peptide IF (10 mg/kg orally) and angiotensin-converting enzyme inhibitors (5 mg/kg orally). In this study, we evaluated the molecular expression levels of BDNF-, GluR1-, and CREB-mediated markers protein expression in 24-week-old SHR rats. The study result showed that HTN-induced AD regulated long-term memory (LTM) loss and neuronal degeneration in the SHR animals. The bioactive peptide-treated animals showed an elevated level of survival proteins. Bioactive peptide IF activate CREB-mediated downstream proteins to regulate synaptic plasticity and neuronal survival in the SHR rat model.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Córtex Cerebral/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Memória de Longo Prazo/efeitos dos fármacos , Compostos Fitoquímicos/uso terapêutico , Doença de Alzheimer/etiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipertensão/complicações , Masculino , Transtornos da Memória/prevenção & controle , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Compostos Fitoquímicos/isolamento & purificação , Ratos , Ratos Endogâmicos SHR , Solanum tuberosum/química
9.
Psychopharmacology (Berl) ; 237(3): 811-823, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31834453

RESUMO

RATIONALE: Inosine is a naturally occurring purine nucleoside formed by adenosine breakdown. This nucleoside is reported to exert potent effects on memory and learning, possibly through its antioxidant and anti-inflammatory actions. OBJECTIVE: The objective is to evaluate the effects of inosine on the behavioral and neurochemical parameters in a rat model of Alzheimer's disease (AD) induced by streptozotocin (STZ). METHODS: Adult male rats were divided into four groups: control (saline), STZ, STZ plus inosine (50 mg/kg), and STZ plus inosine (100 mg/kg). STZ (3 mg/kg) was administered by bilateral intracerebroventricular injection. The animals were treated intraperitoneally with inosine for 25 days. Memory, oxidative stress, ion pump activities, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities and expression were evaluated in the cerebral cortex and hippocampus. RESULTS: The memory impairment induced by STZ was prevented by inosine. An increase in the Na+, K+-ATPase, and Mg-ATPase activities and a decrease in the Ca2+-ATPase activity were induced by STZ in the hippocampus and cerebral cortex, and inosine could prevent these alterations in ion pump activities. Inosine also prevented the increase in AChE activity and the alterations in AChE and ChAT expression induced by STZ. STZ increased the reactive oxygen species, nitrite levels, and superoxide dismutase activity and decreased the catalase and glutathione peroxidase activities. Inosine treatment conferred protection from these oxidative alterations in the brain. CONCLUSIONS: Our findings demonstrate that inosine affects brain multiple targets suggesting that this molecule may have therapeutic potential against cognitive deficit and tissue damage in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Inosina/administração & dosagem , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina/toxicidade
10.
Oxid Med Cell Longev ; 2019: 7860650, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827700

RESUMO

Curcumin is a natural polyphenolic compound widely known to have antioxidant, anti-inflammatory, and antiapoptotic properties. In the present study, we explored the neuroprotective effect of curcumin against lipopolysaccharide- (LPS-) induced reactive oxygen species- (ROS-) mediated neuroinflammation, neurodegeneration, and memory deficits in the adult rat hippocampus via regulation of the JNK/NF-κB/Akt signaling pathway. Adult rats were treated intraperitoneally with LPS at a dose of 250 µg/kg for 7 days and curcumin at a dose of 300 mg/kg for 14 days. After 14 days, the rats were sacrificed, and western blotting and ROS and lipid peroxidation assays were performed. For immunohistochemistry and confocal microscopy, the rats were perfused transcardially with 4% paraformaldehyde. In order to verify the JNK-dependent neuroprotective effect of curcumin and to confirm the in vivo results, HT-22 neuronal and BV2 microglial cells were exposed to LPS at a dose of 1 µg/ml, curcumin 100 µg/ml, and SP600125 (a specific JNK inhibitor) 20 µM. Our immunohistochemical, immunofluorescence, and biochemical results revealed that curcumin inhibited LPS-induced oxidative stress by reducing malondialdehyde and 2,7-dichlorofluorescein levels and ameliorating neuroinflammation and neuronal cell death via regulation of the JNK/NF-κB/Akt signaling pathway both in vivo (adult rat hippocampus) and in vitro (HT-22/BV2 cell lines). Moreover, curcumin markedly improved LPS-induced memory impairment in the Morris water maze and Y-maze tasks. Taken together, our results suggest that curcumin may be a potential preventive and therapeutic candidate for LPS-induced ROS-mediated neurotoxicity and memory deficits in an adult rat model.


Assuntos
Curcumina/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Transtornos da Memória/prevenção & controle , Síndromes Neurotóxicas/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Suplementos Nutricionais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Epilepsy Behav ; 100(Pt A): 106496, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31654940

RESUMO

OBJECT: Temporal lobectomy with amygdalohippocampectomy is the standard surgical treatment for appropriate candidates with medically-intractable temporal lobe epilepsy. More recently, because of the risk of postoperative language/memory decline in a subset of patients with intact memory, a multiple hippocampal transection (MHT) approach has been proposed to preserve function. METHODS: Studies of MHT reporting both Engel and verbal memory outcome measures were included in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting of systematic reviews. Data were extracted on verbal memory function pre- and postoperatively, seizure outcome, and demographic factors. A random effects model was used to determine overall verbal memory function after MHT, and a meta-regression model was applied to identify factors associated with outcome. RESULTS: A total of 114 patients across five studies were included. Engel class I seizure outcome across all studies ranged from 64.7% to 94.7%, with 84 of the 114 patients achieving this outcome. Preoperative verbal memory score was most strongly associated with postoperative verbal memory preservation (p = 0.003). Of 59 patients with full verbal memory outcome scores, 86.8% (95% CI [confidence interval]: 77.6%-96%) had complete preservation of verbal memory relative to preoperative functional baseline. CONCLUSION: Multiple hippocampal transection is an evolving surgical technique. Although the present data are limited, the current systematic review suggests that this approach is effective at preserving verbal memory in patients with good baseline function. Although reasonable seizure outcomes have been reported with MHT, comparison to a well-established procedure such as temporal lobectomy and amydalohippocampectomy must be guided by further evidence.


Assuntos
Epilepsia do Lobo Temporal/cirurgia , Hipocampo/cirurgia , Transtornos da Memória/prevenção & controle , Procedimentos Neurocirúrgicos/métodos , Psicocirurgia/métodos , Hemisferectomia/efeitos adversos , Humanos , Transtornos da Memória/etiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Psicocirurgia/efeitos adversos , Convulsões/cirurgia , Aprendizagem Verbal
12.
Psychiatry Res ; 281: 112577, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31586841

RESUMO

Sleep plays a critical role in body health maintenance, whereas sleep deprivation (SD) negatively affects cognitive function. Cognitive defects mainly memory impairment resulting from sleep deprivation were related to an increase in the level of oxidative stress in the body, including the brain hippocampus region. Edaravone is a potent free radical scavenger having antioxidant effect. In the current study, edaravone's ability to prevent SD induced cognitive impairment was tested in rats. Animals were sleep deprived 8 h/day for 4 weeks. Concurrently, edaravone was administrated intraperitoneally for four weeks. Animals performance during cognitive testing was evaluated to display if edaravone has a role in the prevention of sleep deprivation induced memory impairment. Additionally, the role of antioxidant biomarkers glutathione peroxidase (GPx), catalase, glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG in this effect was investigated. The results showed that SD impaired both short- and long- term memories, and chronic edaravone administration prevented such effect. Additionally, edaravone prevented decreases in hippocampal GPx, catalase, GSH/GSSG ratio and normalized increases in GSSG levels, which were impaired by SD model. In conclusion, current result showed a protective effect of edaravone administration against SD induction that could be related to edaravone's ability to normalizing mechanisms related to oxidative balance.


Assuntos
Antioxidantes/farmacologia , Edaravone/farmacologia , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Privação do Sono/psicologia , Animais , Catalase/efeitos dos fármacos , Glutationa/efeitos dos fármacos , Dissulfeto de Glutationa/efeitos dos fármacos , Glutationa Peroxidase/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
13.
Bull Exp Biol Med ; 167(5): 641-644, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31625062

RESUMO

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.


Assuntos
Ansiolíticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Nootrópicos/farmacologia , Oligopeptídeos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Alcoolismo/tratamento farmacológico , Alcoolismo/etiologia , Alcoolismo/metabolismo , Alcoolismo/fisiopatologia , Animais , Animais não Endogâmicos , Ansiolíticos/síntese química , Fator Neurotrófico Derivado do Encéfalo/agonistas , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/síntese química , Oligopeptídeos/síntese química , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Tuftsina/química , Tuftsina/metabolismo
14.
High Alt Med Biol ; 20(3): 279-292, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31550185

RESUMO

Background: Exposure to hypobaric hypoxia (HH) has been reported to cause neurodegeneration and memory impairment. Hippophae rhamnoides, Prunus armeniaca, and Rhodiola imbricata, the indigenous plants of Indian Trans-Himalaya are widely used in traditional Tibetan and Amchi system of medicine. These are rich sources of diverse bioactive metabolites having prophylactic and therapeutic uses against a wide array of neurodegenerative diseases. The objective of this study was to elucidate the prophylactic and neuroprotective efficacy of formulated phytococktail (PC) against simulated HH-induced neurodegeneration in male Sprague Dawley (SD) rats. Materials and Methods: A PC containing H. rhamnoides fruit pulp, P. armeniaca fruit pulp, and R. imbricata dry root extract (100:50:1) was formulated. The neuroprotective efficacy of PC was evaluated in male SD rats following exposure to 7 day HH at simulated altitude (25,000 ft, 282 mm Hg). Rats were divided into four groups viz., normoxia group (NOR), normoxic group treated with PC (NORPC), 7 day hypoxic group treated with vehicle (7DH), and 7 day hypoxic group treated with PC (7DHPC). Memory impairment and neuromorphological alterations were measured. Targeted protein expression was analyzed by immunoblotting study. Results: PC supplementation significantly reduced the oxidative stress markers during exposure to HH. Spatial memory impairment by HH was significantly ameliorated by PC. HH-induced augmented pyknosis, decreased dendritic arborization, and increased Hoechst-positive neurons in hippocampal CA3 region were significantly ameliorated by PC. Immunoblotting study showed upregulation of BDNF and TrkB expression by PC. PC also prevented the hippocampal neurodegeneration by activating the PI3K/AKT signaling pathway, which leads to GSK-3ß inactivation by its phosphorylation and alleviation of hippocampal Caspase3 expression leading to inhibition of apoptotic neuronal cell death. Conclusion: The present study advocates the potential role of PC as an effective neuroprotective supplement in preventing HH-induced neurodegeneration. Activation of the PI3K/Akt pathway through BDNF/TrkB interaction following PC supplementation after exposure to HH inhibits hippocampal neuronal apoptosis and memory impairment.


Assuntos
Hipóxia Encefálica/tratamento farmacológico , Medicina Tradicional Tibetana , Transtornos da Memória/prevenção & controle , Doenças Neurodegenerativas/prevenção & controle , Fitoterapia , Doença da Altitude/tratamento farmacológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hippophae , Masculino , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Prunus armeniaca , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Rhodiola , Transdução de Sinais , Memória Espacial , Regulação para Cima
15.
Sci Rep ; 9(1): 13252, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520077

RESUMO

With the great extension of the human lifespan in recent times, many aging diseases have inevitably followed. Dementia is one of the most-commom neurodegenerative aging diseases, in which inflammation-related Alzheimer's disease (AD) is the most prevalent cause of dementia. Amyloid accumulation in the brain, which occurs before any clinical presentations, might be the first and key step in the development of AD. However, many clinical trials have attempted to remove amyloid from brains of AD patients, but none has so far been successful. Negatively charged plasmon-activated water (PAW) is created by resonantly illuminated gold (Au) nanoparticles (NPs), which reduce the hydrogen-bonded (HB) structure of water. PAW was found to possess anti-oxidative and anti-inflammatory effects. Herein, we report on an innovative strategy to retard the progression of AD by the daily consumption of PAW instead of normal deionized (DI) water. APPswe/PS1dE9 transgenic mice were treated with PAW or DI water from the age of 5 months for the next 9 months. Encouragingly, compared to DI water-treated mice, mice treated with PAW presented better memory performance on a test of novel object recognition and had a significantly lower amyloid burden according to 18F-florbetapir amyloid-PET and phosphorylated (p)-tau burden according to Western blotting and immunohistochemistry measurements. There were no obvious side effects in PAW-treated mice. Collectively, our findings support that PAW was able to reduce the amyloid and p-tau burden and improve memory in an AD mouse model. However, the protein levels of molecules involved in amyloid metabolism and oligomeric amyloid did not change. We propose that the effects of PAW of reducing the amyloid burden and improving memory function cannot be attributed to synthesis/degradation of amyloid-ßprotein but probably in preventing aggregation of amyloid-ß proteins or other mechanisms, including anti-inflammation. Further applications of PAW in clinical trials to prevent the progression of AD are being designed.


Assuntos
Doença de Alzheimer/complicações , Modelos Animais de Doenças , Transtornos da Memória/prevenção & controle , Nanopartículas Metálicas/administração & dosagem , Água/química , Precursor de Proteína beta-Amiloide/fisiologia , Animais , Progressão da Doença , Ouro/química , Humanos , Ligação de Hidrogênio , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Nanopartículas Metálicas/química , Camundongos , Camundongos Transgênicos , Presenilina-1/fisiologia , Ressonância de Plasmônio de Superfície
16.
Anesth Analg ; 129(5): 1365-1373, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31517674

RESUMO

BACKGROUND: Early life anesthesia exposure results in long-term cognitive deficits in rats. Environmental enrichment consisting of social housing, a stimulating environment, and voluntary exercise can rescue this deficit. We hypothesized that exercise alone is sufficient to rescue the cognitive deficit associated with perinatal anesthesia. METHODS: Postnatal day 7 male rats (P7) underwent isoflurane (Iso) or sham exposure and were subsequently weaned at P21. They were then singly housed in a cage with a running wheel or a fixed wheel. After 3 weeks of exercise, animals underwent behavioral testing for spatial and recognition memory assessments. Animals were killed at various time points to accomplish either bromodeoxyuridine (BrdU) labeling or quantitative real-time polymerase chain reaction (qRT-PCR) to quantify brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels. RESULTS: Postweaning voluntary exercise rescued the long-term spatial memory deficit associated with perinatal Iso exposure. Iso-sedentary animals did not discriminate the goal quadrant, spending no more time than chance during the Barnes maze probe trial (1-sample t test, P = .524) while all other groups did (1-sample t test, PIso-exercise = .033; Pcontrol [Con]-sedentary = .004). We did not find a deficit in recognition memory tasks after Iso exposure as we observed previously. BrdU incorporation in the adult hippocampus of Iso-sedentary animals was decreased compared to sedentary controls (Tukey P = .005). Exercise prevented this decrease, with Iso-exercise animals having more proliferation than Iso-sedentary (Tukey P < .001). There was no effect of exercise or Iso on BDNF mRNA in either the cortex or hippocampus (cortex: FExercise[1,32] = 0.236, P = .631; FIso [1,32] = 0.038, P = .847; FInteraction [1,32] = 1.543, P = .223; and hippocampus: FExercise[1,33] = 1.186, P = .284; FIso [1,33] = 1.46, P = .236; FInteraction[1,33] = 1.78, P = .191). CONCLUSIONS: Exercise restores BrdU incorporation and rescues a spatial memory deficit after early life anesthesia exposure. This demonstrates sufficiency of exercise alone in the context of environmental enrichment to recover a behavioral phenotype after a perinatal insult.


Assuntos
Anestésicos Inalatórios/toxicidade , Isoflurano/toxicidade , Transtornos da Memória/prevenção & controle , Condicionamento Físico Animal , Memória Espacial/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Life Sci ; 235: 116819, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473194

RESUMO

AIMS: Traumatic brain injury (TBI) not only induces physiological disabilities but also leads to cognitive impairment. However, no effective therapeutic approach for TBI-related memory decline exists. In this study, we treated TBI mice with cinnamic acid (CNA) to detect whether CNA is able to rescue the memory deficits induced by TBI and to explore the potential mechanisms. MAIN METHODS: Mice were divided into the following groups: the sham group, the TBI group, the TBI + CNA group and the CNA group. Basic physiological parameters, neurological severity score and brain water content were analyzed. The Morris water maze and inhibitory avoidance step-down task were used to determine learning and memory. Golgi staining was used to measure alterations in dendritic spines. Western blot analysis and a commercial kit were used to detect the content and activity of HDAC2. qPCR was used to detect the relative level of miR-455. KEY FINDINGS: CNA did not affect physiological function but effectively restored neurological function and brain edema. CNA alleviated the memory impairments induced by TBI in both the Morris water maze and step-down task. CNA also recovered abnormalities in the synapses of TBI mice by suppressing the activity of HDAC2. Furthermore, CNA did not alter HDAC mRNA because it promoted the expression of miR-455-3p, a miRNA that regulates HDAC2 at the posttranscriptional level. SIGNIFICANCE: The application of CNA effectively treats TBI-induced memory deficits by increasing miR-455-3p and by inhibiting HDAC2.


Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/complicações , Cinamatos/farmacologia , Histona Desacetilase 2/metabolismo , Transtornos da Memória/prevenção & controle , MicroRNAs/genética , Transmissão Sináptica/efeitos dos fármacos , Animais , Histona Desacetilase 2/genética , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
18.
J Pharmacol Exp Ther ; 371(2): 250-259, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31488603

RESUMO

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/toxicidade , Inibidores da Fosfodiesterase 4/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Técnicas de Introdução de Genes , Hipocampo/patologia , Humanos , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Distribuição Aleatória
19.
Artigo em Inglês | MEDLINE | ID: mdl-31494630

RESUMO

Background Short-term memory impairment is a neurodegenerative disease associated with oxidative stress. Bryophyllum pinnatum (Lam.) Oken of the family Crassulaceae is traditionally used in the treatment of diseases, such as cough, wounds, and kidney diseases. This study evaluates the effect of the aqueous extract of B. pinnatum (AEBP) leaves on acetylcholinesterase activity in carbon tetrachloride (CCl4)-induced short-term memory impairment in rats. Methods Thirty male Wistar albino rats were used in this study and were divided into six groups (n=5). Group I served as control, group II rats were induced with CCl4, while groups III-V animals were pretreated with silymarin (25 mg/kg body weight), 25 and 50 mg/kg body weight AEBP leaves, respectively, once daily by oral gavage for 14 days prior to a single intraperitoneal injection of CCl4. Animals in group VI received 50 mg/kg body weight AEBP only by oral gavage. Results Administration of carbon tetrachloride significantly increased (p<0.05) spontaneous alternation and locomotor function in rats when compared with the control group. Also, the levels of acetylcholinesterase, adenosine deaminase, and malondialdehyde were increased in CCl4-administered rats, with reduction in both enzymatic and nonenzymatic antioxidant levels. However, pretreatment of rats with AEBP leaves, at tested doses, prevented these changes. Conclusions The increased antioxidant status and the inhibition of acetylcholinesterase activity show that AEBP leaves improve learning memory and stabilizes memory impairment caused by CCl4.


Assuntos
Tetracloreto de Carbono/toxicidade , Kalanchoe , Transtornos da Memória/prevenção & controle , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Adenosina Desaminase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Masculino , Malondialdeído/metabolismo , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Silimarina/farmacologia , Água/química
20.
J Neural Transm (Vienna) ; 126(10): 1321-1328, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31377952

RESUMO

Previously, we found out that in ovariectomized female rats, estrogen and progesterone produce a memory deficit which is reverted by the intrahippocampal administration of allopregnanolone. Here, we study the possible interplay between allopregnanolone and hippocampal serotonergic activity. Ovariectomized rats injected subcutaneously with estrogen and progesterone were subsequently injected in the dorsal hippocampus with vehicle, allopregnanolone alone or allopregnanolone shortly after 8OH-DPAT, a predominantly 5HT1A-7 receptor agonist. Then, the subjects were sequentially tested in: (1) an inhibitory avoidance task and (2) K+-evoked [3H]-serotonin ex vivo release through superfusion experiments. Allopregnanolone increased the K+-evoked [3H]-serotonin release compared to control. 8OH-DPAT infusions reversed the effects of allopregnanolone on memory and K+-evoked [3H]-serotonin release. These results suggest that allopregnanolone memory improvement could be mediated, at least in part, through modulation of the hippocampal serotonergic system reactivity.


Assuntos
Estrogênios/farmacologia , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Pregnanolona/uso terapêutico , Progesterona/farmacologia , Serotonina/metabolismo , Animais , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Transtornos da Memória/induzido quimicamente , Ovariectomia/efeitos adversos , Pregnanolona/farmacologia , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/farmacologia
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