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Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder characterized by impaired cognition, memory loss, and altered personality. Many of the available pharmaceutical treatments do not alter the onset of disease progression. Recently, alternatives to developed drug candidates have been explored including medicinal plants and herbal treatments for the treatment of AD. This article examines the role of herbal plant extracts and the neuroprotective effects as alternative modes of intervention for AD progression. These extracts contain key metabolites that culminate alterations in AD progression. The traditional plant extracts explored in this article induce a variety of beneficial properties, including antioxidants, anti-inflammatory, and enhanced cognition, while also inducing activity on AD drug targets such as Aß degradation. While these neuroprotective aspects for AD are relatively recent, there is great potential in the drug discovery aspect of these plant extracts for future use in AD treatment.
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Lung cancer is the most prevalent and observed type of cancer in Xuanwei County, Yunnan, South China. Lung cancer in this area is called Xuanwei lung cancer. However, its pathogenesis remains largely unknown. To date, a number of studies have shown that microRNA (miR)218 functions as a tumor suppressor in multiple types of cancer. However, the role of miR218 and its regulatory gene network in Xuanwei lung cancer have yet to be investigated. The current study identified that the expression levels of miR218 in XWLC05 cells were markedly lower compared with those in immortalized lung epithelial BEAS2B cells. The present study also demonstrated that overexpression of miR218 could decrease cell proliferation, invasion, viability and migration in Xuanwei lung cancer cell line XWLC05 and NSCLC cell line NCIH157. Additionally, the results revealed that overexpression of miR218 could induce XWLC05 and NCIH157 cell apoptosis by arresting the cell cycle at G2/M phase. Finally, the present study demonstrated that overexpression of miR218 could lead to a significant increase in phosphatase and tensin homolog (PTEN) and YY1 transcription factor (YY1), and a decrease in Bcell lymphoma 2 (BCL2) and BMI1 protooncogene, polycomb ring finger (BMI1) at the mRNA and protein level in XWLC05 and NCIH157 cell lines. However, we did not observe any remarkable difference in the roles of miR218 and miR218mediated regulation of BCL2, BMI1, PTEN and YY1 expression in the progression of Xuanwei lung cancer. In conclusion, miR218 could simultaneously suppress cell proliferation and tumor invasiveness and induce cell apoptosis by increasing PTEN and YY1 expression, while decreasing BCL2 and BMI1 in Xuanwei lung cancer. The results demonstrated that miR218 might serve a vital role in tumorigenesis and progression of Xuanwei lung cancer and overexpression of miR218 may be a novel approach for the treatment of Xuanwei lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação para Baixo , Neoplasias Pulmonares/genética , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , China , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismoRESUMO
OBJECTIVE: As a noninvasive and nonpharmacological therapeutic approach, superficial acupuncture (SA) is a special method of acupuncture. In this study, using nonlinear dynamics and multivariate statistics, we studied the electroencephalography (EEG) of primary insomnia under SA intervention to investigate how brain regions change. METHOD: This study included 30 adults with primary insomnia. They underwent superficial acupuncture at the Shangen acupoint. The EEG signals were collected for 10 minutes at each state, including the resting state, the intervention state, and the postintervention state. The data were conducted using nonlinear dynamics (including approximate entropy (ApEn) and correlation dimension (CD)) and multivariate statistics. RESULT: The repeated-measures ANOVA results showed that both ApEn and CD values were not significantly different at the three states (p > 0.05). The paired t-test results showed that the ApEn values of electrodes O2 (the right occipital lobe) at the postintervention state have decreased, compared with the resting state (p < 0.05), and no difference was detected in CD (p > 0.05). The cluster analysis results of ApEn showed that patients' EEG has changed from the right prefrontal lobe (electrode Fp2) to the right posterior temporal lobe (electrode T6) and finally to the right occipital lobe (electrode O2), before, during, and after the SA intervention. In addition, the factor analysis results of CD revealed that patients' EEG of all brain regions except for the occipital lobes has changed to the frontal lobes and anterior temporal and frontal lobes from pre- to postintervention. CONCLUSION: SA activated the corresponding brain regions and reduced the complexity of the brain involved. It is feasible to use nonlinear dynamics analysis and multivariate statistics to examine the effects of SA on the human brain.
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Alzheimer's disease (AD) includes several hallmarks comprised of amyloid-ß (Aß) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aß deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.
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Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Arginase/metabolismo , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/metabolismo , Células Mieloides/fisiologia , Animais , Arginase/genética , Autofagia , Comportamento Animal , Modelos Animais de Doenças , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Transgênicos , Inflamação Neurogênica , Transdução de SinaisRESUMO
BACKGROUND: Traumatic brain injury (TBI) is a widespread public health problem and a signature injury of our military in modern conflicts. Despite the long-term effects of even mild brain injuries, an effective treatment remains elusive. Coffee and several of its compounds, including caffeine, have been identified as having neuroprotective effects in studies of neurodegenerative disease. Given the molecular similarities between TBI and neurodegenerative disease, we have devised a study to test a nanocoffee extract in the treatment of a mouse model of mild TBI. RESULTS: After a single injury and two subsequent injections of nanocoffee, we identified treatment as being associated with improved behavioral outcomes, favorable molecular signaling changes, and dendritic changes suggestive of improved neuronal health. CONCLUSIONS: We have identified coffee extracts as a potential viable multifaceted treatment approach to target the secondary injury associated with TBI.
Assuntos
Concussão Encefálica/prevenção & controle , Coffea/química , Aprendizagem em Labirinto/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Concussão Encefálica/patologia , Concussão Encefálica/psicologia , Córtex Cerebral/metabolismo , Dendritos/patologia , Hipocampo/metabolismo , Masculino , Camundongos , Nanopartículas/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/química , Sonicação , Água/químicaRESUMO
Acupuncture at the SJ5 (Waiguan) acupoint has neuroprotective effects in cerebral infarction, but the underlying mechanism remains poorly understood. Here, we analyzed gene expression in healthy rat cerebellum using a pathway-focused DNA microarray to screen 113 genes associated with 18 signal transduction pathways. After 20 minutes of acupuncture at SJ5, the expression of Bcl-2 and Birc1b mRNA was markedly increased. This was confirmed by real-time reverse transcription PCR. Furthermore, western blot analysis showed that Bcl-2 protein expression remained high in the cerebellum until at least 2 hours after cessation of acupuncture. These findings indicate that acupuncture at SJ5 exerts neuroprotective effects by regulating the expression of anti-apoptotic gene Bcl-2.
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The last three decades have documented preclinical and clinical data supporting the use of acupuncture in relieving symptoms of many diseases, including allergies, infections, and neurological disorders. The advent of electroacupuncture has not only modernized the practice of acupuncture, but also has improved its efficacy, especially for producing analgesic-like effects. Although the mechanism of action of acupuncture-induced analgesia remains largely unknown, several lines of investigation have implicated modulation of pain processes via brain opioid signaling and neuroimmunoregulatory pathways. Here, we review key findings demonstrating the efficacy and underlying mechanisms of acupuncture-induced analgesia. In particular, we discuss potent analgesic effects of acupuncture via neural pain processes through inhibition of microglial activation. The safe and effective use of acupuncture stands as a nonpharmacological alternative for induction of analgesia, which has direct clinical applications, especially for pain-related diseases.
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Analgesia por Acupuntura , Microglia/imunologia , Neuroimunomodulação , Manejo da Dor , Dor/imunologia , HumanosRESUMO
CONTEXT: Telomerase is a critical enzyme that is involved in aging and cancer and that is thought to be a part of multiple neurological diseases. OBJECTIVE: To investigate the telomerase response in the brain to acupuncture, the study examined the levels of expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling molecules, including tyrosine kinase receptor Β (TrkB), p75 neurotrophin receptor (p75NTR), protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK1/2), and nuclear factor κΒ (NF-κΒ). DESIGN: Both telomerase-deficient (Tercâ»/â») mice (Tercâ»/â» group) and normal, wild-type (WT) mice (WT group) were randomly assigned to 1 of 3 subgroups, 1 receiving acupuncture (acupuncture subgroup), 1 receiving sham acupuncture therapy (sham subgroup), and 1 receiving no treatment (control subgroup). SETTING: The study occurred at the University of South Florida Health Byrd Alzheimer's Institute (Tampa, FL, USA). INTERVENTION: The 2 acupuncture subgroups received acupuncture at the stomach 36 (ST-36) position for 30 min/d for 4 d. For the 2 sham groups, the sham point was set at a location approximately 3 mm to the lateral side of the tail on the gluteus muscle following the same schedule. OUTCOME MEASURES: After 4 d, the mice were sacrificed, and the brain tissues were collected. The protein levels in the hippocampus and dentate gyrus (DG) of each mouse were determined by western blotting and immunostaining assays. RESULTS: The Tercâ»/â» group showed downregulated hippocampal BDNF expression compared with the WT mice. Acupuncture at ST-36 for 4 d upregulated BDNF, TrkB, p75NTR, Akt, and ERK1/2 in the DG and hippocampus of the telomerase-deficient mice, but that result was not seen in the WT mice with normally functioning telomerase. CONCLUSIONS: The use of acupuncture in pathologies associated with telomerase deficiencies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), may provide some benefit in terms of eliciting better clinical responses. The research team believes that result occurs through the activation of BDNF and its downstream signaling pathways in populations of patients who exhibit low telomerase activity.
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Terapia por Acupuntura/métodos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , RNA/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Telomerase/metabolismo , Animais , Camundongos , Camundongos Knockout , Distribuição Aleatória , Transdução de SinaisRESUMO
Lycium barbarum berries, also named wolfberry, Fructus lycii, and Goji berries, have been used in the People's Republic of China and other Asian countries for more than 2,000 years as a traditional medicinal herb and food supplement. L. barbarum polysaccharides (LBPs) are the primary active components of L. barbarum berries and have been reported to possess a wide array of pharmacological activities. Herein, we update our knowledge on the main pharmacological activities and possible molecular targets of LBPs. Several clinical studies in healthy subjects show that consumption of wolfberry juice improves general wellbeing and immune functions. LBPs are reported to have antioxidative and antiaging properties in different models. LBPs show antitumor activities against various types of cancer cells and inhibit tumor growth in nude mice through induction of apoptosis and cell cycle arrest. LBPs may potentiate the efficacy of lymphokine activated killer/interleukin-2 combination therapy in cancer patients. LBPs exhibit significant hypoglycemic effects and insulin-sensitizing activity by increasing glucose metabolism and insulin secretion and promoting pancreatic ß-cell proliferation. They protect retinal ganglion cells in experimental models of glaucoma. LBPs protect the liver from injuries due to exposure to toxic chemicals or other insults. They also show potent immunoenhancing activities in vitro and in vivo. Furthermore, LBPs protect against neuronal injury and loss induced by ß-amyloid peptide, glutamate excitotoxicity, ischemic/reperfusion, and other neurotoxic insults. LBPs ameliorate the symptoms of mice with Alzheimer's disease and enhance neurogenesis in the hippocampus and subventricular zone, improving learning and memory abilities. They reduce irradiation- or chemotherapy-induced organ toxicities. LBPs are beneficial to male reproduction by increasing the quality, quantity, and motility of sperm, improving sexual performance, and protecting the testis against toxic insults. Moreover, LBPs exhibit hypolipidemic, cardioprotective, antiviral, and antiinflammatory activities. There is increasing evidence from preclinical and clinical studies supporting the therapeutic and health-promoting effects of LBPs, but further mechanistic and clinical studies are warranted to establish the dose-response relationships and safety profiles of LBPs.
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Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Lycium/química , Polissacarídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Especificidade por SubstratoRESUMO
The traditional Chinese medicinal formula BDL301 has been used to inhibit inflammation for hundreds of years. The development of colorectal cancer and chronic inflammation are closely related. In this study, we investigated whether BDL301 could inhibit tumor growth. We found that angiogenesis and tumor growth were both inhibited in vivo. In addition, apoptosis was induced and the signal transducer and activator of transcription-3 (STAT3) pathway were suppressed in the colorectal cancer cells in vitro and in vivo by BDL301. This study demonstrates that BDL301 exerted significant anticancer activity by inhibiting the STAT3 pathways and inducing apoptosis in colorectal cancer cells.
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Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Feminino , Células HCT116 , Humanos , Imuno-Histoquímica , Masculino , Medicina Tradicional Chinesa , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
There is an increasing prevalence of Alzheimer's disease (AD), which has become a public health issue. However, the underlying mechanisms for the pathogenesis of AD are not fully understood, and the current therapeutic drugs cannot produce acceptable efficacy in AD patients. Previous animal studies have shown that coffee (Coff), caffeine (Caff), and melatonin (Mel) have beneficial effects on AD. Disturbed circadian rhythms are observed in AD, and chronotherapy has shown promising effects on AD. In this study, we examined whether a combination of Coff or Caff plus Mel produced a synergistic/additive effect on amyloid-ß (Aß) generation in Neuro-2a (N2a)/amyloid precursor protein (APP) cells and the possible mechanisms involved. Cells were treated with Coff or Caff, with or without combined Mel, with three different chronological regimens. In regimen 1, cells were treated with Coff or Caff for 12 hours in the day, followed by Mel for 12 hours in the night. For regimen 2, cells were treated with Coff or Caff plus Mel for 24 hours, from 7 am to 7 am the next day. In regimen 3, cells were treated with Coff or Caff plus Mel with regimen 1 or 2 for 5 consecutive days. The extracellular Aß40/42 and Aß oligomer levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. The expression and/or phosphorylation levels of glycogen synthase kinase 3ß (GSK3ß), Erk1/2, PI3K, Akt, Tau, Wnt3α, ß-catenin, and Nrf2 were detected by Western blot assay. The results showed that regimen 1 produced an additive antiamyloidogenic effect with significantly reduced extracellular levels of Aß40/42 and Aß42 oligomers. Regimen 2 did not result in remarkable effects, and regimen 3 showed a less antiamyloidogenic effect compared to regimen 1. Coff or Caff, plus Mel reduced oxidative stress in N2a/APP cells via the Nrf2 pathway. Coff or Caff, plus Mel inhibited GSK3ß, Akt, PI3K p55, and Tau phosphorylation but enhanced PI3K p85 and Erk1/2 phosphorylation in N2a/APP cells. Coff or Caff, plus Mel downregulated Wnt3α expression but upregulated ß-catenin. However, Coff or Caff plus Mel did not significantly alter the production of T helper cell (Th)1-related interleukin (IL)-12 and interferon (IFN)-γ and Th2-related IL-4 and IL-10 in N2a/APP cells. The autophagy of cells was not affected by the combinations. Taken together, combination of Caff or Coff, before treatment with Mel elicits an additive antiamyloidogenic effects in N2a/APP cells, probably through inhibition of Aß oligomerization and modulation of the Akt/GSK3ß/Tau signaling pathway.
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Peptídeos beta-Amiloides/antagonistas & inibidores , Cafeína/farmacologia , Café/química , Melatonina/metabolismo , Multimerização Proteica/efeitos dos fármacos , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Cafeína/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Melatonina/agonistas , Camundongos , Simulação de Acoplamento Molecular , Agregação Patológica de Proteínas/tratamento farmacológico , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway.
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Terapia por Acupuntura , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Animais , Humanos , Proteínas Tirosina Quinases/metabolismoRESUMO
Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.
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Interações Ervas-Drogas , Preparações de Plantas/farmacocinética , Plantas Medicinais/metabolismo , Humanos , Preparações Farmacêuticas/metabolismoRESUMO
Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-ß levels/deposition through suppression of both ß- and γ-secretase. Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AßPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines. The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Aß production. We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.
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Cafeína/uso terapêutico , Transtornos Cognitivos/sangue , Transtornos Cognitivos/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/sangue , Inibidores de Fosfodiesterase/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Cafeína/sangue , Café/metabolismo , Transtornos Cognitivos/etiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Testes Neuropsicológicos , Fragmentos de Peptídeos/sangue , Presenilina-1/genética , Teofilina/sangue , Fatores de TempoRESUMO
Epidemiologic studies have increasingly suggested that caffeine/coffee could be an effective therapeutic against Alzheimer's disease (AD). We have utilized a transgenic mouse model for AD in well-controlled studies to determine if caffeine and/or coffee have beneficial actions to protect against or reverse AD-like cognitive impairment and AD pathology. AD mice given caffeine in their drinking water from young adulthood into older age showed protection against memory impairment and lower brain levels of the abnormal protein (amyloid-beta; Abeta) thought to be central to AD pathogenesis. Moreover, "aged" cognitively-impaired AD mice exhibited memory restoration and lower brain Abeta levels following only 1-2 months of caffeine treatment. We believe that the cognitive benefits of chronic caffeine administration in AD mice are due to caffeine itself, and not metabolites of caffeine; this, because our long-term administration of theophylline to AD mice provided no cognitive benefits. In acute studies involving AD mice, one oral caffeine treatment quickly reduced both brain and plasma Abeta levels - similarly rapid alterations in plasma Abeta levels were seen in humans following acute caffeine administration. "Caffeinated" coffee provided to AD mice also quickly decreased plasma Abeta levels, but not "decaffeinated" coffee, suggesting that caffeine is critical to decreasing blood Abeta levels. Caffeine appears to provide its disease-modifying effects through multiple mechanisms, including a direct reduction of Abeta production through suppression of both beta- and gamma-secretase levels. These results indicate a surprising ability of moderate caffeine intake (the human equivalent of 500 mg caffeine or 5 cups of coffee per day) to protect against or treat AD in a mouse model for the disease and a therapeutic potential for caffeine against AD in humans.
Assuntos
Doença de Alzheimer/prevenção & controle , Cafeína/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Café/metabolismo , Doença de Alzheimer/complicações , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Humanos , Camundongos , Presenilina-1/metabolismoRESUMO
Despite numerous studies, there is no definitive evidence that high-frequency electromagnetic field (EMF) exposure is a risk to human health. To the contrary, this report presents the first evidence that long-term EMF exposure directly associated with cell phone use (918 MHz; 0.25 w/kg) provides cognitive benefits. Both cognitive-protective and cognitive-enhancing effects of EMF exposure were discovered for both normal mice and transgenic mice destined to develop Alzheimer's-like cognitive impairment. The cognitive interference task utilized in this study was designed from, and measure-for-measure analogous to, a human cognitive interference task. In Alzheimer's disease mice, long-term EMF exposure reduced brain amyloid-beta (Abeta) deposition through Abeta anti-aggregation actions and increased brain temperature during exposure periods. Several inter-related mechanisms of EMF action are proposed, including increased Abeta clearance from the brains of Alzheimer's disease mice, increased neuronal activity, and increased cerebral blood flow. Although caution should be taken in extrapolating these mouse studies to humans, we conclude that EMF exposure may represent a non-invasive, non-pharmacologic therapeutic against Alzheimer's disease and an effective memory-enhancing approach in general.
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Doença de Alzheimer/terapia , Transtornos Cognitivos/prevenção & controle , Modelos Animais de Doenças , Magnetoterapia/métodos , Doença de Alzheimer/complicações , Doença de Alzheimer/psicologia , Animais , Transtornos Cognitivos/complicações , Transtornos Cognitivos/psicologia , Campos Eletromagnéticos , Camundongos , Camundongos TransgênicosRESUMO
The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer's transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin's cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.