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1.
Medicine (Baltimore) ; 99(4): e18507, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977846

RESUMO

BACKGROUND: Although memory loss and other symptoms of dementia pose tremendous burdens on patients and societies, there is currently no cure for dementia. METHODS: We conducted a systematic review and meta-analysis of the anti-dementia effects of Danggui-Shaoyao-San (DSS), which is derived from natural resources. We searched for randomized controlled trials (RCTs) from inception to June 2019. We searched PubMed, Embase, Korean databases (Research Information Service System and Oriental Medicine Advanced Searching Integrated System), Chinese databases (China Knowledge Resource Integrated Database and Wanfang Database), and Japanese databases (CiNii and J-STAGE). Studies were included if they were a RCT, investigated the efficacy of DSS or its modified form, and included participants with dementia. Use of DSS with other treatment (eg, acupuncture, anti-dementia drugs, etc) was included. Items of each trial were evaluated by 2 independent reviewers. Data were pooled by using random-effect models. RESULTS: A total of 482 studies were identified, and 5 eligible studies for Alzheimer disease (AD) and 4 studies for vascular dementia (VD) were included in the final analysis, representing a total of 567 participants. As for AD, pooled results of the Mini-Mental State Examination (MMSE) (mean differences [MD] 4.60; 95% confidence interval [CI] 4.29, 4.91) and activities of daily living (MD 11.40; 95% CI 10.94, 11.86) favored DSS. DSS had synergistic effect with acupuncture over acupuncture alone in MMSE (MD 1.69; 95% CI 1.05, 2.34), Hasegawa Dementia Scale (MD.62; 95% CI -0.20, 1.44), and activities of daily living (MD 2.38; 95% CI 1.92, 2.85). In VD, pooled results showed a significant difference in the score of dementia scales such as MMSE and Hasegawa Dementia Scale compared with nootropic drugs. DSS significantly reduced symptoms (odds ratio 5.02, 95%, CI 2.76-9.11) in patients with VD. The respective size of each RCTs was small and some included studies were of low quality due to their limited description on methodological issues. CONCLUSION: These estimates suggest that DSS provides clinically important reductions in symptoms of AD and VD and can be a promising anti-dementia drug candidate.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Atividades Cotidianas , Terapia por Acupuntura/métodos , China , Terapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Testes de Estado Mental e Demência , Nootrópicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Medicine (Baltimore) ; 98(50): e18326, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852125

RESUMO

BACKGROUND: Vascular dementia (VaD) is the second most common cause of dementia. The treatment of VaD still remains a challenge so far. Traditional Chinese Herbal medicine is a promising therapy due to their multiple components and targets. Shenmayizhi decoction (SMYZD), a Chinese Herbal prescription, has been reported its effective in alleviating cognitive dysfunction in clinical practice. However, strong clinical research of SMYZD in the treatment of VaD was lack. Therefore, we design this study to evaluate the adjuvant role of SMYZD in the treatment of VaD. METHODS: This is a multicenter, randomized, blind, controlled trial. A total of 196 eligible patients will be assigned to receive Ginkgo biloba extracts (GBEs) plus SMYZD granule or GBEs plus SMYZD mimetic granule in a 1:1 ratio. The duration of the trial will be 12 weeks, and a follow-up will be performed at the 24th week. The primary outcomes are the National Institute of Health stroke scale (NIHSS) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcomes include the Mini-Mental State Examination (MMSE), the traditional Chinese Medicine (TCM) syndrome scale, Activities of Daily Living (ADL), concentrations of hypersensitive C-reactive protein (Hs-CRP), neuron-specific enolase (NSE) and homocysteine (HCY) in serum. Researchers will record any adverse events throughout the trial. DISCUSSION: This study will provide evidences to evaluate the efficacy and safety of SMYZD in combination with GBEs in treatment of VaD, as well as the adjuvant role of SMYZD in combination. TRIAL IS REGISTERED AT CHINESE CLINICAL TRIAL REGISTRY: ChiCTR1800017359.


Assuntos
Demência Vascular/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Atividades Cotidianas , Idoso , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Extratos Vegetais/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
Braz J Med Biol Res ; 52(11): e8371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721903

RESUMO

Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirrolidinas/administração & dosagem , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Demência Vascular/metabolismo , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
4.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3423-3428, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602904

RESUMO

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Diterpenos/farmacologia , NF-kappa B/metabolismo , Fenantrenos/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo , Animais , Compostos de Epóxi/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
5.
Medicine (Baltimore) ; 98(34): e16920, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441874

RESUMO

RATIONALE: Vascular cognitive impairment (VCI) is a common cause of dementia. Research suggests that hereditary factors (gene mutations) play an important role in the pathogenesis of VCI, and a mutation of the NOTCH3 locus is frequently identified in affected patients. Herein, we report the case of a patient with confirmed VCI associated with a NOTCH3 exon 33 gene mutation and review the relevant VCI literature. PATIENT CONCERNS: A 48-year-old man presented to our neurology clinic with gradually progressive cognitive impairment. DIAGNOSES: Brain magnetic resonance imaging revealed multiple punctate hyperintensities in the patient's periventricular white matter. Genetic analysis showed a c.6744C > T, p. Ala2223Val substitution in exon 33 of the NOTCH3 gene. We diagnosed thepatient with VCI secondary to a NOTCH3 gene mutation. INTERVENTIONS: Donepezil (5 mg) and memantine (5 mg) daily. OUTCOMES: The patient showed symptom improvement at his 3-month and 6-month follow-up appointments. LESSONS: This patient may have a new type of mutation that is different from the one seen in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, although it involves a NOTCH3 defect. We propose that the entire NOTCH3 gene should be sequenced in patients with suspected hereditary VCI. This practice could facilitate the discovery of newpathogenic mutations and diseases.


Assuntos
Demência Vascular/genética , Receptor Notch3 , Disfunção Cognitiva/etiologia , Demência Vascular/complicações , Demência Vascular/tratamento farmacológico , Donepezila/administração & dosagem , Humanos , Masculino , Memantina/administração & dosagem , Pessoa de Meia-Idade , Mutação , Nootrópicos/administração & dosagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
6.
J Korean Acad Nurs ; 49(3): 317-328, 2019 Jun.
Artigo em Coreano | MEDLINE | ID: mdl-31266928

RESUMO

PURPOSE: The purpose of this study was to identify the effect of ghrelin on memory impairment in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. METHODS: Randomized controlled groups and the posttest design were used. We established the representative animal model of vascular dementia caused by bilateral common carotid artery occlusion and administered 80 µg/kg ghrelin intraperitoneally for 4 weeks. First, behavioral studies were performed to evaluate spatial memory. Second, we used molecular biology techniques to determine whether ghrelin ameliorates the damage to the structure and function of the white matter and hippocampus, which are crucial to learning and memory. RESULTS: Ghrelin improved the spatial memory impairment in the Y-maze and Morris water maze test. In the white matter, demyelination and atrophy of the corpus callosum were significantly decreased in the ghrelin-treated group. In the hippocampus, ghrelin increased the length of hippocampal microvessels and reduced the microvessels pathology. Further, we confirmed angiogenesis enhancement through the fact that ghrelin treatment increased vascular endothelial growth factor (VEGF)-related protein levels, which are the most powerful mediators of angiogenesis in the hippocampus. CONCLUSION: We found that ghrelin affected the damaged myelin sheaths and microvessels by increasing angiogenesis, which then led to neuroprotection and improved memory function. We suggest that further studies continue to accumulate evidence of the effect of ghrelin. Further, we believe that the development of therapeutic interventions that increase ghrelin may contribute to memory improvement in patients with vascular dementia.


Assuntos
Demência Vascular/tratamento farmacológico , Grelina/uso terapêutico , Animais , Demência Vascular/patologia , Modelos Animais de Doenças , Grelina/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neovascularização Fisiológica , Distribuição Aleatória , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
Cochrane Database Syst Rev ; 3: CD003154, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30891742

RESUMO

BACKGROUND: Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD. OBJECTIVES: To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs). SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS: We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales. MAIN RESULTS: Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls. AUTHORS' CONCLUSIONS: We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.


Assuntos
Demência/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Acatisia Induzida por Medicamentos/etiologia , Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Humanos , Memantina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Suspensão de Tratamento
8.
Semin Neurol ; 39(2): 153-166, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30925609

RESUMO

Dementia is a state of cognitive dysfunction which leads to functional decline. It is a syndrome caused by several medical and neurological causes, but most cases of dementia are due to "primary dementias." Primary dementias are neurological diseases whose manifestations are predominantly cognitive. Most primary dementias are caused by neurodegenerative proteinopathies where an accumulation of misfolded proteins leads to neuronal loss, neuroinflammation and glial reaction. Each proteinopathy is characterized by the type of protein implicated in its pathophysiology. Neurodegenerative dementias include the most prevalent cause of dementia-Alzheimer's disease-as well as Lewy body dementia, Parkinson's disease dementia, frontotemporal dementias, and prion diseases. Vascular dementia, especially small vessel disease, though not a neurodegenerative condition, is often grouped together with primary dementias. Each type of proteinopathy, characterized by the location and nature of misfolded protein accumulation, may correspond to a particular clinical phenotype. The correspondence between pathologies and clinical phenotypes is not exclusive, and there is a large degree of overlap. Although in the research setting the clinicopathological construct is on the wane, in the clinic it is the most practical way of approaching primary dementias. In this article, we introduce the clinicopathological construct, the understanding of which will form the basis of the other articles in this volume.


Assuntos
Doença de Alzheimer , Demência Vascular , Demência , Demência Frontotemporal , Doença por Corpos de Lewy , Doenças Priônicas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Demência/tratamento farmacológico , Demência/metabolismo , Demência/patologia , Demência/fisiopatologia , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Demência Vascular/patologia , Demência Vascular/fisiopatologia , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/fisiopatologia , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Doenças Priônicas/fisiopatologia
9.
J Pharmacol Sci ; 139(3): 223-230, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30799178

RESUMO

Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-ß1-42 peptides (Aß1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aß1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3ß (pSer9-GSK3ß) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aß1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3ß and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aß1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3ß and IDE.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Ginsenosídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Animais , Transtornos Cognitivos/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Demência Vascular/fisiopatologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Insulisina/metabolismo , Masculino , Memória/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Dtsch Med Wochenschr ; 144(3): 156-160, 2019 02.
Artigo em Alemão | MEDLINE | ID: mdl-30703832

RESUMO

Antidementia therapy: The clinical use of acetylcholinesterase inhibitors (AChE-I) for the symptomatic treatment of mild to moderate Alzheimer's dementia is recognized worldwide, despite its modest effectiveness. AChE-I may be continued to be used into severe stages of the dementia. In moderate to severe Alzheimer's dementia, the NMDA-receptor-antagonist Memantin is indicated.Lewy body dementia is treated as Alzheimer's disease; for Parkinson's dementia, there is a separate indication for rivastigmin. A worsening in motor symptoms may occur. There is no evidence-based antidementia drug therapy for frontotemporal or vascular dementia.Future Therapeutic Strategies: Disease modification is a major focus of current clinical trials. There are several clinical trials targeting anti-amyloid (phase 3) or anti-tau strategies. However, other therapeutic targets are persued, too. In current clinical trials, mild cognitive impairment due to Alzheimer's disease is targeted as the most meaningful study population.Implications for practice: At present, there just is symptomatic anti-dementive drug therapy available for Alzheimer's dementia, Parkinson's dementia and Lewy body dementia. Despite its modest effect sizes, treatment with these drugs is clinically relevant and seems to be cost-effective.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Demência Vascular/tratamento farmacológico , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Memantina/uso terapêutico
11.
Molecules ; 24(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669383

RESUMO

Hwangryunhaedok-tang (HRT) is a traditional oriental herbal formula used in Asian countries for treating inflammatory diseases and controlling fever. Our present study aimed to determine whether HRT has therapeutic effects for patients with vascular dementia (VaD) using a bilateral common carotid artery occlusion (BCCAO) rat model and assessing spatial memory impairment and activation of neuroinflammation. BCCAO was performed in male Sprague Dawley rats to induce VaD, and oral HRT was administered daily for 30 d. Our data showed that HRT ameliorated BCCAO-induced memory and cognitive impairment in behavioral tests. In addition, HRT reversed cholinergic dysfunction and neuronal damage in the hippocampus of BCCAO rats. Furthermore, HRT attenuated microglial activation and reduced the phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) induced by BCCAO. Simultaneous high-performance liquid chromatography analysis of HRT using index compounds from the herbal composition revealed that both HRT ethanol extract and commercial HRT granules primarily comprise geniposide, baicalin, and berberine. Our study showed that HRT administration resulted in the prevention of neuronal injury induced by BCCAO through improvement of cholinergic dysfunction and inhibition of neuroinflammatory responses, suggesting that HRT may have potential as a treatment for VaD.


Assuntos
Demência Vascular/metabolismo , Demência Vascular/psicologia , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetilcolina/metabolismo , Animais , Colinérgicos/química , Colinérgicos/farmacologia , Cromatografia Líquida de Alta Pressão , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estrutura Molecular , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Ratos
12.
J Pharmacol Sci ; 139(2): 105-111, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30642751

RESUMO

Recent studies suggested that Chotosan has ameliorative effects on vascular dementia through antioxidative pathways. Nevertheless, no systematic pharmacological research was conducted to evaluate the contribution of nuclear factor-E2-related factor 2 (Nrf2), a crucial regulator of antioxidative system, on Chotosan-induced neuroprotection invascular dementia. The present study aimed to investigate the neuroprotective effect of Chotosan on vascular dementia and reveal the possible molecular mechanism involving Nrf2. We found that Chotosan treatment could ameliorate memory impairment and reduce neuron cell loss induced by common carotid artery occlusion surgery. Furthermore, Chotosan could significantly reverse reactive oxygen species production, neuronal apoptosis and microglia over-activation in hippocampus. In addition, Chotosan enhanced Nrf2 expression and its nuclear translocation as well as its downstream antioxidant protein expression, NAD(P)H/quinone oxidoreductase 1 and heme oxygenase-1. These findings suggest that Chotosan exert neuroprotection in an animal model of vascular dementia via activating Nrf2-mediated antioxidant pathway. Chotosan may serve as a potential candidate and promising Nrf2 activator for treating vascular dementia.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Demência Vascular/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais
13.
Acta Pharmacol Sin ; 40(4): 425-440, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30382185

RESUMO

Vascular dementia (VD) results from accumulated damage in the vascular system, which is characterized by progressive impairments in memory and cognition and is second only to Alzheimer's disease (AD) in prevalence among all types of dementia. In contrast to AD, there is no FDA-approved treatment for VD owing to its multiple etiologies. In this study, we investigated whether CZ-7, a new derivative of Claulansine F (Clau F) with verified neuroprotective activity in vitro, could ameliorate the cognitive impairment of rats with permanent occlusion of bilateral common carotid arteries (2VO) and its potential mechanisms of action. The 2VO rats were orally administered CZ-7 (10, 20, 40 mg/kg) from day 27 to day 53 post-surgery. Morris water maze tests conducted at day 48-51 revealed that CZ-7 administration significantly reduced the escape latency in 2VO rats. After the rats were sacrificed on day 53, morphological studies using Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that administration of CZ-7 markedly attenuated the pathological changes in CA1-CA3 area of the hippocampus, including neuronal cell loss, nuclear shrinkage, and dark staining of neurons, and significantly decreased the chronic cerebral hypoperfusion-induced cell loss. Klüver-Barrera staining study revealed that CZ-7 administration significantly improved the white matter lesions. 8-OHdG and reactive oxygen species (ROS) immunofluorescent analyses showed that CZ-7 administration significantly decreased oxidative stress in CA1-CA3 area of the hippocampus. Finally, we found that the CZ-7-improved oxidative stress might be mediated via the Nrf2 pathway, evidenced by the double immunofluorescent staining of Nrf2 and the elevation of expression levels of oxidative stress proteins HO-1 and NQO1. In conclusion, CZ-7 has therapeutic potential for VD by alleviating oxidative stress injury through Nrf2-mediated antioxidant responses.


Assuntos
Antioxidantes/metabolismo , Artéria Carótida Primitiva/efeitos dos fármacos , Demência Vascular/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Artéria Carótida Primitiva/metabolismo , Artéria Carótida Primitiva/patologia , Demência Vascular/metabolismo , Demência Vascular/patologia , Masculino , Estrutura Molecular , Ratos , Ratos Wistar
14.
Neurochem Int ; 127: 103-112, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30592970

RESUMO

BACKGROUND: and purpose: In this study, we employed a multiple microinfarction (MMI) based vascular dementia (VaD) model in aged rats and tested the therapeutic effects of Sildenafil, a phosphodiesterase type 5 inhibitor, on cognitive decline, white matter damage, autophagy and inflammatory response associated with VaD. METHODS: Male, aged (16-18 months) Wistar rats were subjected to MMI (800 ± 100, 70-100 µm cholesterol crystals injected into the internal carotid artery) and treated with or without Sildenafil (2 mg/kg, i.p) starting at 24 h after MMI daily for 28 days. Four experimental groups were employed: Sham control, Sham + Sildenafil, MMI, and MMI + Sildenafil. A battery of cognitive tests were performed and rats were sacrificed at 28 days after MMI for immunohistochemical evaluation and PCR assay. RESULTS: Sildenafil treatment in aged MMI rats significantly improves short term memory evaluated by the novel object recognition test and improves spatial learning and memory in the Morris water maze test compared to aged control MMI rats. Sildenafil treatment of aged MMI rats significantly increases axon and myelin density in the corpus callosum and white matter bundles in the striatum, increases oligodendrocyte and oligodendrocyte progenitor cell number in the corpus callosum, cortex and striatum, and increases synaptic protein expression in the cortex and striatum compared to aged control MMI rats. In addition, Sildenafil treatment of MMI in aged rats significantly decreases Beclin1 expression and inflammatory factors Monocyte chemoattractant protein-1 and Interleukin-1ß expression in brain. Sildenafil treatment in aged rats does not improve cognitive outcome compared to aged sham control rats. CONCLUSIONS: Sildenafil treatment of MMI in aged rats significantly improves cognition and memory at 1 month after MMI. Sildenafil treatment increases axon and myelin density, increases Synaptophysin expression, decreases autophagic activity and exerts anti-inflammatory effects which in concert may contribute to cognitive improvement in aged rats subjected to MMI.


Assuntos
Envelhecimento/fisiologia , Demência Vascular/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Citrato de Sildenafila/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Demência Vascular/metabolismo , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/fisiologia , Bainha de Mielina/efeitos dos fármacos , Ratos Wistar
15.
Cochrane Database Syst Rev ; 12: CD010284, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30520514

RESUMO

BACKGROUND: Traditional Chinese herbal medicine (TCHM) is widely used for treating vascular dementia (VaD) in China. Recent studies of a number of TCHMs have demonstrated in vitro biological activity and therapeutic effects in animals, but the published clinical evidence has not been systematically appraised. OBJECTIVES: To evaluate the efficacy and safety of TCHMs listed in either the Chinese Pharmacopoeia (CP) or the Chinese National Essential Drug List (NEDL) that are used to treat VaD. A secondary aim was to identify promising TCHMs for further clinical research. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialised Register (on 14 March 2018) and also several Chinese biomedical databases: the Chinese Biological Medicine Database (January 1979 to May 2015), Wanfang database (January 1998 to May 2015), Chongqing VIP Information Co. Ltd or Weipu (January 1998 to May 2015) and the Chinese National Knowledge Infrastructure (January 1979 to May 2015). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of TCHMs compared to placebo, to Western medicine (WM) or to routine therapy for VaD risk factors. Eligible participants were men and women aged 18 years and above, diagnosed with VaD by any of the following four criteria: (1) Diagnostic and Statistical Manual of Mental Disorders (DSM) versions III, III-R, IV, IV-TR; (2) National Institute of Neurological Disorders and Stroke (NINDS-AIREN); (3) International Classification of Diseases 9 or 10; (4) the Hachinski or the Modified Hachinski Ischaemic Score. We required the use of an imaging technique to differentiate VaD from other dementias. We excluded (1) trials with participants diagnosed with mixed dementia or those that did not use an imaging technique to ascertain VaD; (2) trials of NEDL-listed Gingko biloba or Huperzine A as experimental interventions, to avoid duplication of existing Cochrane Reviews; (3) trials using acupuncture alone as the experimental intervention; (4) trials using another CP- or NEDL-listed TCHM (except for Huperzine A and Gingko which are popular in Western practice) as the control intervention; and (5) trials using purely non-pharmacological interventions as the control intervention unless explicitly described as 'routine therapy for VaD risk factors'. DATA COLLECTION AND ANALYSIS: We assessed the risks of bias using the Cochrane 'Risk of bias' tool and adapted the Outcome Reporting Bias in Trials (ORBIT) classification system for outcome reporting bias. We assessed TCHM effects on five clinically important outcomes: cognition, global performance, safety, activities of daily living and behaviour and summarised the effects using mean differences for continuous outcomes and risk ratios or risk differences for binary outcomes. We stratified the studies into those that estimated the TCHM versus 'no treatment' effect and those that estimated the TCHM versus the WM effect, with further stratification by the specific TCHM tested or by one of the four modes of action. We pooled using a random-effects model. Due to substantial clinical and design heterogeneity, we did not estimate an 'overall TCHM effect'. MAIN RESULTS: We only found studies (47 studies, 3581 participants) for 18 of the 29 eligible TCHMs as defined by our inclusion criteria. All were superiority trials conducted in China between 1997 and 2013, with most employing a two-arm parallel design with sample sizes ranging from 26 to 240 and a median treatment duration of 12 weeks (range: 2 to 24 weeks).We found that reporting and trial methodology were generally poor; in particular, there was a lack of information on randomisation, an absence of blinding of participants and outcome assessors and incomplete reporting of adverse events (AEs). None of the 30 trials published from 2007 onwards adopted the CONSORT recommendations for reporting RCTs of herbal interventions.We found seven TCHMs which each had potentially large benefits in studies estimating the TCHM versus 'no treatment' effect and in studies estimating the TCHM versus the WM effect. Two TCHMs (NaoXinTong and TongXinLuo) were common to both groups. Three of these TCHMs - Nao XinTong, NaoMaiTai and TongXinLuo - had the strongest evidence to justify further research. Two TCHMs (NaoMaiTai and TongXinLuo) had a 5% or more increased risk of AEs compared to the 'no Treatment' control, but the quality of this evidence was poor. AUTHORS' CONCLUSIONS: We found moderate- to very low-quality evidence of benefit and harm of TCHMs for VaD. Methodological inadequacies need to be addressed by better conducted and reported trials. We identified NaoMaiTai, NaoXinTong and TongXinLuo as warranting special research priority.


Assuntos
Demência Vascular , Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Demência Vascular/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Medicine (Baltimore) ; 97(51): e13760, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572524

RESUMO

BACKGROUND: Vascular dementia (VaD) is the 2nd most common subtype of dementia after Alzheimer disease. Currently, there are no medications approved for treating patients with VaD. Tianmabianchunzhigan (TMBCZG) tablet is an active ingredient extracted from Gastrodia that has been reported to improve memory and other cognition. And the TBMCZG has been approved clinical trial with patients with VaD by center for drug evaluation of China (CFDA). To evaluate the efficacy, safety, and tolerability of TMBCZG tablets in the treatment of mild to moderate VaD, we designed and reported the methodology for a 24-week, randomized, double-blind, parallel, placebo-controlled, multicenter trial. METHODS: A total of 160 patients with mild to moderate VaD will be enrolled. After a 2-week run-in period, the eligible patients will be randomized to receive either TMBCZG high-dose group (TBMCZG 3 tablets, twice per day); TMBCZG middle-dose group (TMBCZG 2 tablets and placebo 1 tablet twice per day); TMBCZG low-dose group (TMBCZG 1 tablet and placebo 2 tablets, twice per day); placebo group (placebo 3 tablets, twice per day) for 24 weeks, with a follow-up 12 weeks after withdrawn drug treatment. The primary efficacy measurement will be the vascular dementia assessment scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes scale. The secondary efficacy measurements will include the mini mental state examination and activities of daily living. Adverse events will also be reported. DISCUSSION: This randomized trial will be the 1st rigorous study on the efficacy and safety of TMBCZG tablets for treating cognitive symptoms in patients with VaD using a rational design. TRIAL REGISTRATION: ClinicalTrials.gov NCT03230071. Registered on July 26, 2017.


Assuntos
Demência Vascular/tratamento farmacológico , Gastrodia/química , Extratos Vegetais/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Extratos Vegetais/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Eur Rev Med Pharmacol Sci ; 22(16): 5377-5384, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30178865

RESUMO

OBJECTIVE: L-3-n-butylphthalide (L-NBP) is a type of anti-ischemic cranial nerve protective drug that may act on vascular dementia (VD). Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT/PKB) signaling pathway can up-regulate B-cell lymphoma 2 (Bcl-2) expression, reduce reactive oxygen species (ROS) production, and alleviate cell apoptosis. This study aimed at investigating the role of L-NBP on neurological function and cell apoptosis in VD mouse through regulating PI3K/AKT signaling pathway. MATERIALS AND METHODS: The mice were divided into four groups, including Sham, VD, VD + solvent, and VD + L-NBP. HT22 cells were cultured in vitro and treated by ischemia/reperfusion (I/R). HT22 cells were divided into four groups, including I/R, VD + solvent, VD + L-NBP, and VD + L-NBP + LY294002 groups. Phosphorylated AKT (p-AKT) and Bcl-2 expressions were tested. ROS content in hippocampus tissue was detected by flow cytometry. Cell apoptosis was evaluated by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay. RESULTS: ROS content and cell apoptosis increased, while p-AKT and Bcl-2 expressions reduced in hippocampus tissue from VD group compared with sham group. L-NBP significantly up-regulated p-AKT and Bcl-2 expressions and decreased ROS content and cell apoptosis in hippocampus tissue. I/R treatment markedly induced HT22 cell apoptosis and ROS production, and reduced p-AKT and Bcl-2 expressions. L-NBP treatment markedly up-regulated p-AKT and Bcl-2 levels, restrained cell apoptosis, and reduced ROS content in TH22 cells intervened by I/R. LY294002 apparently attenuated the protective effect of L-NBP on HT22 cells. CONCLUSIONS: L-NBP protects VD by up-regulating PI3K/AKT signaling pathway, elevating Bcl-2 expression, reducing nerve cell apoptosis, and restraining ROS production.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Demência Vascular/tratamento farmacológico , Animais , Demência Vascular/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Eur J Pharmacol ; 834: 118-125, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30012500

RESUMO

This study examined the potential of the selective extra-synaptic α5-GABAA receptor inhibitor S44819 (Egis-13529) to improve cognitive performance in preclinical models of vascular cognitive impairment (VCI). Chronic hypoperfusion of the brain in mice was induced by permanent occlusion of the right common carotid artery (rUCO). rUCO induced impairments of cognitive function in the object recognition test (OR) and the rewarded T-maze (RTM). In both tests, a single oral treatment with S44819 (OR - 0.1-3 mg/kg, RTM - 1-3 mg/kg p.o.) significantly reduced the effect of rUCO. Long-term treatment with S44819 (1-10 mg/kg twice daily p.o. for 14 days), that was initiated 24 h after surgery and was followed by a 10- or 13-day wash-out period, fully prevented the decline of cognitive performance of rUCO mice. In rats, occlusion of the middle cerebral artery (MCA) for 30 min caused a significantly diminished performance in the OR. This was prevented by S44819 given p.o. 15 mg/kg twice daily for 8 days, starting 7 days after surgery and tested following a 7-day wash-out period. Taken together, S44819 markedly and stably improved reference and working memory impaired by rUCO in mice. In rats, the compound effectively suppressed the development of cognitive impairment after mild stroke. In conclusion, as longer-term administration led to a persistent reversal of the cognitive deficits, it appears that S44819 may have symptomatic, as well as disease-modifying effects in models of VCI. Proof of concept is therefore provided for testing S44819 in the therapy of VCI and post-stroke dementia in humans.


Assuntos
Benzodiazepinas/farmacologia , Demência Vascular/tratamento farmacológico , Antagonistas de Receptores de GABA-A/farmacologia , Oxazóis/farmacologia , Receptores de GABA-A/metabolismo , Animais , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Cognição/efeitos dos fármacos , Demência Vascular/metabolismo , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Receptores de GABA-A/administração & dosagem , Antagonistas de Receptores de GABA-A/uso terapêutico , Masculino , Camundongos , Oxazóis/administração & dosagem , Oxazóis/uso terapêutico , Ratos , /fisiologia
19.
Psychiatry Res ; 267: 281-288, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29945070

RESUMO

Vascular dementia (VaD) is characteristic of chronic brain ischemia and progressive memory decline, which has a high incidence in the elderly. However, there are no effective treatments for VaD, and the underlying mechanism of its pathogenesis remains unclear. This study investigated the effects of a synthetic cannabinoid receptor agonist WIN55,212-2 (WIN) on VaD, and molecular mechanisms of the effects. VaD model was induced by 2-vessel occlusion (2VO). Spatial reference learning was evaluated by the Morris water maze, and recognition memory was assessed using the novel object recognition test. Autophagy-related proteins [microtubule-associated protein 1 light chain 3 (LC-3) and Beclin-1] were examined by immunohistochemistry and Western blot. Caspase-3 was detected by Western blot. Inflammatory factors, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß), were estimated by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. VaD increased the levels of LC-3, Beclin-1, and inflammatory factors, which were reversed by chronic treatment with WIN. WIN decreased the expression of Capase-3, and improved the learning and memory impairment of VaD rats. These data indicate that WIN exerts a neuroprotective effect on the cognitive deficits of VaD rats, which may be associated with the suppression of excessive autophagy and inflammation.


Assuntos
Autofagia/efeitos dos fármacos , Benzoxazinas/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Autofagia/fisiologia , Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Demência Vascular/patologia , Demência Vascular/psicologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley
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