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1.
Alzheimers Res Ther ; 12(1): 15, 2020 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-31954399

RESUMEN

BACKGROUND: Metabotropic glutamate subtype 5 receptors (mGluR5) modulate synaptic transmission and may constitute an important therapeutic target in Alzheimer's disease (AD) by mediating the synaptotoxic action of amyloid-ß oligomers. We utilized the positron emission tomography (PET) radioligand [18F]FPEB to investigate mGluR5 binding in early AD. METHODS: Sixteen individuals with amnestic mild cognitive impairment (MCI) due to AD or mild AD dementia who were positive for brain amyloid were compared to 15 cognitively normal (CN) participants who were negative for brain amyloid. Diagnostic groups were well balanced for age, sex, and education. Dynamic PET scans were acquired for 60 min, starting at 60 min after the initial administration of up to 185 MBq of [18F]FPEB using a bolus-plus-constant-infusion method (Kbol = 190 min). Equilibrium modeling with a cerebellum reference region was used to estimate [18F]FPEB binding (BPND) to mGluR5. Analyses were performed with and without corrections for gray matter atrophy and partial volume effects. RESULTS: Linear mixed model analysis demonstrated a significant effect of group (p = 0.011) and the group × region interaction (p = 0.0049) on BPND. Post hoc comparisons revealed a significant reduction (43%) in mGluR5 binding in the hippocampus of AD (BPND = 0.76 ± 0.41) compared to CN (BPND = 1.34 ± 0.58, p = 0.003, unpaired t test) participants, and a nonsignificant trend for a reduction in a composite association cortical region in AD (BPND = 1.57 ± 0.25) compared to CN (BPND = 1.86 ± 0.63, p = 0.093) participants. Exploratory analyses suggested additional mGluR5 reductions in the entorhinal cortex and parahippocampal gyrus in the AD group. In the overall sample, hippocampal mGluR5 binding was associated with episodic memory scores and global function. CONCLUSIONS: [18F]FPEB-PET revealed reductions in hippocampal mGluR5 binding in early AD. Quantification of mGluR5 binding in AD may expand our understanding of AD pathogenesis and accelerate the development of novel biomarkers and treatments.

2.
Artículo en Inglés | MEDLINE | ID: mdl-31806426

RESUMEN

OBJECTIVE: To investigate associations between statin use and cognitive change, as well as diagnostic conversion, in individuals with cognitively normal (CN) status, mild cognitive impairment (MCI), and dementia due to Alzheimer disease (AD-dementia). METHODS: A multicenter cohort study with 1629 adults 48 to 91 years old with CN status, early MCI (EMCI), late MCI (LMCI), or AD-dementia at baseline followed prospectively for 24 months. Statin use was assessed at baseline, and cognition was measured over time with a composite memory score, a composite executive function score, and a global cognition score (Alzheimer's Disease Assessment Scale). Conversion to a more impaired diagnostic category was determined by clinician assessment. Repeated measures linear mixed-effects models were used to evaluate associations between statin use and change in cognition over time. Cox proportional hazards models were used to evaluate associations between statin use and time to diagnostic conversion. All models were stratified by baseline diagnostic group. RESULTS: Statin use was not associated with change in cognitive measures for CN, LMCI, or AD-dementia participants. Among EMCI participants, statin use was associated with a significantly slower rate of decline on the memory composite, but no other cognitive measure. Statin use was not associated with time to conversion for any diagnostic group. CONCLUSIONS: This study did not support an association between statin use and diagnostic conversion but suggested a possible association between statin use and cognitive change in EMCI. Additional randomized clinical trials of statins may be warranted in the prodromal EMCI stage of AD.

3.
Prog Mol Biol Transl Sci ; 165: 139-165, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31481161

RESUMEN

Current understanding of Alzheimer's disease (AD) pathogenesis relies on the observed accumulations of amyloid ß and phosphorylated tau aggregates that are thought to play key roles in initiating or propagating disease. However, other processes including changes in synaptic proteins and neurotransmitter loss have been suggested as important etiologies or contributors. Positron emission tomography (PET) imaging allows in vivo investigations of molecular changes associated with AD. PET imaging with multiple radiotracers can be used in combination with other modalities such as magnetic resonance imaging (MRI), and with assessments of cognition and neuropsychiatric symptoms to investigate the molecular underpinnings of AD. Studies of synaptic protein changes may improve the understanding of disease mechanisms and provide valuable markers of disease progression and therapeutic efficacy. This chapter will illustrate the importance of in vivo molecular imaging in the study of AD with a specific emphasis on PET and radioligands for several non-amyloid targets.

4.
Am J Pharm Educ ; 83(5): 6435, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31333246

RESUMEN

Objective. To develop a brief instrument for academic pharmacists or physicians to use in assessing postgraduate residents' knowledge of polypharmacy. Methods. Five clinicians used a modified Delphi process to create a 26-item multiple-choice test to assess knowledge of polypharmacy in geriatric primary care. The test was distributed to 74 participants: 37 internal medicine (MD) residents, six nurse practitioner (NP) residents, nine primary care attendings, 12 pharmacists and pharmacy residents, and 10 geriatrics attendings and fellows. Construct validity was assessed using factor analysis and item response theory. Overall group differences were examined using a Kruskal-Wallis test, and between group differences were assessed using the Wilcoxon rank sum test. Results. The response rate for the survey was 89%. Factor analysis resulted in a one factor solution. Item response theory modeling yielded a 12-item and six-item test. For the 12-item test, the mean scores of geriatricians and pharmacists (88%) were higher than those of MD and NP residents (58%) and primary care attendings (61%). No differences were found between MD and NP residents and primary care attendings. Findings for the six-item test were similar. Conclusion. Both the 12-item and six-item versions of this polypharmacy test showed acceptable internal consistency and known groups validity and could be used in other academic settings. The similar scores between MD and NP residents and primary care attendings, which were significantly lower than scores for pharmacists and geriatricians, support the need for increased educational interventions.

5.
J Gen Intern Med ; 34(7): 1220-1227, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30972554

RESUMEN

BACKGROUND: Polypharmacy and potentially inappropriate medications (PIMs) are increasingly common and associated with adverse health effects. However, post-graduate education in polypharmacy and complex medication management for older adults remain limited. OBJECTIVE: The Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) polypharmacy clinic was created to provide a platform for teaching internal medicine (IM) and nurse practitioner (NP) residents about outpatient medication management and deprescribing for older adults. We aimed to assess residents' knowledge of polypharmacy and perceptions of this interprofessional education intervention. DESIGN: A prospective cohort study with an internal comparison group. PARTICIPANTS: IM residents and NP residents; Veterans ≥ 65 years and taking ≥ 10 medications. INTERVENTION: IMPROVE consists of a pre-clinic conference, shared medical appointment, individual appointment, and interprofessional precepting model. MAIN MEASURES: We assessed residents' performance on a pre-post knowledge test, residents' qualitative assessment of the educational impact of IMPROVE, and the number and type of medications discontinued or decreased. KEY RESULTS: The IMPROVE intervention group (n = 18) had a significantly greater improvement in test scores than the control group (n = 18) (14% ± 15% versus - 1.3% ± 16%) over a period of 6 months (Wilcoxon rank sum, p = 0.019). In focus groups, residents (n = 17) reported perceived improvements in knowledge and skills, noting that the experience changed their practice in other clinical settings. In addition, residents valued the unique interprofessional experience. Veterans (n = 71) had a median of 15 medications (IQR 12-19), and a median of 2 medications (IQR 1-3) was discontinued. Vitamins, supplements, and cardiovascular medications were the most commonly discontinued medications, and cardiovascular medications were the most commonly decreased in dose or frequency. CONCLUSIONS: Overall, IMPROVE is an effective model of post-graduate primary care training in complex medication management and deprescribing that improves residents' knowledge and skills, and is perceived by residents to influence their practice outside the program.

6.
Am J Geriatr Psychiatry ; 26(12): 1258-1267, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30314940

RESUMEN

OBJECTIVE: To investigate optimal cutoff scores and the effects of normative adjustments on the performance of the Montreal Cognitive Assessment (MoCA) as a screening instrument for Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease (AD-dementia). METHODS: 499 adults 48 to 91 years-old enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and were administered the MoCA during baseline. Participants were classified as either cognitively normal (CN), MCI, or AD-dementia by clinical assessment. Receiver operating characteristic (ROC) analyses were performed using raw MoCA scores, education-adjusted MoCA scores, and a regression-based adjustment derived from the National Alzheimer's Coordinating Center data (NACC). Test performance characteristics were calculated for various cutoffs after each normative correction method. RESULTS: Areas under the curve (AUC) were similar for raw, education-adjusted, and NACC-adjusted MoCA scores, and demonstrated minimal improvement when adjustments of increasing complexity were applied. Our results suggest that the optimal cutoff score for distinguising MCI is 24 and for distinguising AD-dementia is 22. CONCLUSIONS: This study adds to the understanding of how normative adjustments affect the sensitivity and specificity of the MoCA. Suggested corrections based on education alone do not yield improved test characteristics, but small improvements are attained when a regression-based correction that accounts for age, sex, and education is applied. Furthermore, optimal cutoffs for distinguishing CN from MCI or CN from AD-dementia were lower than previously reported. Optimal cutoffs to detect MCI and AD-dementia may vary in different populations, and further study is needed to determine appropriate use of the MoCA as a screening tool.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Pruebas de Estado Mental y Demencia/normas , Pruebas Neuropsicológicas/normas , Psicometría/normas , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad
7.
Neurobiol Aging ; 70: 117-124, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30007160

RESUMEN

This study evaluated the effect of the alpha-2A-adrenoceptor agonist guanfacine on prefrontally mediated cognitive functions, as well as quality of life and global function in healthy older participants. One hundred twenty-three participants aged 75 years and older were randomly assigned to guanfacine 0.5 mg, 0.1 mg, or placebo daily for 12 weeks. The primary outcome measure was the change in z-score for 6 prefrontal executive function tasks over 12 weeks (PEF6). Neither dose of guanfacine improved PEF6 z-score relative to placebo. The rate of mean change (95% confidence interval) in PEF6 z-score over 12 weeks was 0.270 (0.159, 0.380) for placebo, compared with 0.121 (0.011, 0.232) for guanfacine 0.1 mg (p = 0.06, compared to placebo) and 0.213 (0.101, 0.324) for 0.5 mg (p = 0.47). Neither dose of guanfacine improved the quality of life or global function relative to placebo. Among common adverse events, only dry mouth was significantly more frequent on guanfacine compared to placebo. Guanfacine failed to ameliorate prefrontal cognitive function in older individuals, who were cognitively normal for age.


Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Guanfacina/uso terapéutico , Corteza Prefrontal/fisiopatología , Factores de Edad , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/fisiopatología , Método Doble Ciego , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Calidad de Vida , Resultado del Tratamiento
8.
JAMA Neurol ; 75(10): 1215-1224, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30014145

RESUMEN

Importance: Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective: To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants: This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11C-PiB) for ß-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures: Outcomes were 11C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results: Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] ß-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] ß-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). Conclusions and Relevance: To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.


Asunto(s)
Envejecimiento , Enfermedad de Alzheimer , Amnesia , Disfunción Cognitiva , Hipocampo , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Tomografía de Emisión de Positrones/métodos , Piridinas , Pirrolidinonas , Sinapsis , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amnesia/diagnóstico por imagen , Amnesia/metabolismo , Amnesia/patología , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Estudios Transversales , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Memoria Episódica , Sinapsis/metabolismo , Sinapsis/patología
9.
Dement Geriatr Cogn Disord ; 45(3-4): 232-242, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29886490

RESUMEN

BACKGROUND: We investigated the relationship between sleep disturbance and cognitive decline or clinical conversion in individuals with normal cognition (CN), as well as those with mild cognitive impairment (MCI) and dementia due to Alzheimer disease (AD-dementia). METHODS: Secondary analysis of 1,629 adults between 48 and 91 years of age with up to 24 months of follow-up from the ADNI (Alzheimer's Disease Neuroimaging Initiative), a longitudinal cohort study. RESULTS: Sleep disturbance was not associated with decline in memory, executive function, or global cognition. The presence of sleep disturbance did not significantly increase the risk of diagnostic conversion in CN, early MCI, or late MCI participants. CONCLUSION: This study investigated the effect of sleep disturbance on cognitive decline using several outcomes and does not support the hypothesis that sleep disturbance predicts subsequent cognitive decline.


Asunto(s)
Enfermedad de Alzheimer , Cognición , Disfunción Cognitiva , Función Ejecutiva , Trastornos del Sueño-Vigilia , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/epidemiología , Estadística como Asunto , Estados Unidos/epidemiología
10.
Stroke ; 49(6): 1419-1425, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29712881

RESUMEN

BACKGROUND AND PURPOSE: For suspected large vessel occlusion patients efficient transfer to centers that provide endovascular therapy (ET) is critical to maximizing treatment opportunity. Our objective was to examine associations between transfer time, modes of transfer, ET, and outcomes within a hub-and-spoke telestroke network. METHODS: Patients with ischemic stroke were included if transferred to a single hub hospital between January 2011 and October 2015 with National Institutes of Health Stroke Scale>6, onset<12 hours from hub arrival with complete clinical, imaging, and transfer data. Transfer time was the interval between initiation of telestroke consult and arrival at the hub. Algorithms were created for ideal transfer times; ideal time was subtracted from actual time to calculate delay. We examined bivariate relationships between transfer time and several clinical outcomes and used multivariable regression modeling to explore possible predictors of delay. RESULTS: Of 234 patients that met inclusion criteria, 51% were transferred by ambulance and 49% by helicopter; 27% underwent ET (36% achieved modified Rankin Scale score of 0-2 at 90 days). Median actual transfer time was 132 minutes (interquartile range, 103-165), compared with median ideal transfer time at 102 minutes (interquartile range, 96-123). Longer transfer time was associated with decreased likelihood of undergoing ET (odds ratio, 0.990; P=0.003). Nocturnal transfer (18:00 to 06:00 hours) was associated with significantly longer delay (ß=20.5; P<0.0005), whereas intravenous tissue-type plasminogen activator (tPA) delivery at spoke hospital was not. The median delay for nocturnal transfer was 31 minutes (interquartile range, 11-51), compared with daytime at 14 minutes (interquartile range, -9 to 36). CONCLUSIONS: Within a large telestroke network, there was an association between longer transfer time and decreased likelihood of undergoing ET. Nocturnal transfers were associated with a substantial delay relative to daytime transfers. In contrast, delivery of tPA was not associated with delays, underscoring the impact of effective protocols at spoke hospitals. More efficient transfer may enable higher ET treatment rates. Metrics and protocols for transfer, especially at night, may improve transfer times.


Asunto(s)
Transferencia de Pacientes , Accidente Cerebrovascular/terapia , Trombectomía , Factores de Tiempo , Anciano , Anciano de 80 o más Años , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Terapia Trombolítica/métodos , Activador de Tejido Plasminógeno/uso terapéutico
11.
Neurobiol Aging ; 61: 207-214, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29111487

RESUMEN

Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to ß-amyloid (Aß) burden in brain regions preferentially affected by AD and whether Aß burden is associated with gray-matter (GM) fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50-65 years with a first-degree family history of AD (APOE genotype ε4ε4 [n = 15], ε3ε4 [n = 15], and ε3ε3 [n = 15]) underwent [11C]PiB positron emission tomography scans to quantify cortical Aß, brain magnetic resonance imaging, and neuropsychological testing. APOE ε4ε4 participants demonstrated significantly higher cortical Aß burden than APOE ε3ε3 (p < 0.001). Furthermore, cortical Aß burden was inversely associated with cortical GM fraction (p = 0.017) but not episodic memory performance. In cognitively normal, middle-aged individuals, Aß burden is significantly associated with GM fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Corteza Cerebral/metabolismo , Genotipo , Sustancia Gris/patología , Memoria Episódica , Anciano , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Cognición , Femenino , Sustancia Gris/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Riesgo
12.
Neuropharmacology ; 81: 134-41, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24508710

RESUMEN

Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke. We determined the effects of central and peripheral administration of C21 on the cerebral damage and neurological deficits in rats elicited by endothelin-1 induced middle cerebral artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained in rats injected systemically (intraperitoneal) with C21 either before or after endothelin-1 induced MCAO. The protective effects of C21 were reversed by central administration of an AT2R inhibitor, PD123319. While C21 did not alter cerebral blood flow at the doses used here, peripheral post-stroke administration of this agent significantly attenuated the MCAO-induced increases in inducible nitric oxide synthase, chemokine (C-C) motif ligand 2 and C-C chemokine receptor type 2 mRNAs in the cerebral cortex, indicating that the cerebroprotective action is associated with an anti-inflammatory effect. These results strengthen the view that AT2R agonists may have potential therapeutic value in ischemic stroke, and provide the first evidence of cerebroprotection induced by systemic post stroke administration of a selective AT2R agonist.


Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II/uso terapéutico , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/complicaciones , Circulación Cerebrovascular/efectos de los fármacos , Endotelina-1/toxicidad , Accidente Cerebrovascular , Animales , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/etiología , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Imidazoles/uso terapéutico , Masculino , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peroxidasa/genética , Peroxidasa/metabolismo , Piridinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/prevención & control , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Factores de Tiempo
13.
Exp Physiol ; 99(2): 442-53, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24142453

RESUMEN

NEW FINDINGS: What is the central question of this study? Activation of angiotensin-converting enzyme 2, resulting in production of angiotensin-(1-7) and stimulation of its receptor, Mas, exerts beneficial actions in a number cardiovascular diseases, including ischaemic stroke. A potential beneficial role for angiotensin-(1-7) in haemorrhagic stroke has not previously been reported. What is the main finding and its importance? Central administration of angiotensin-(1-7) into stroke-prone spontaneously hypertensive rats, a model of haemorrhagic stroke, increases lifespan and improves the neurological status of these rats, as well as decreasing microglial numbers in the striatum (implying attenuation of cerebral inflammation). These actions of angiotensin-(1-7) have not previously been reported and identify this peptide as a potential new therapeutic target in haemorrhagic stroke. Angiotensin-(1-7) [Ang-(1-7)] exerts cerebroprotective effects in ischaemic stroke, and this action is associated with a blunting of intracerebral inflammatory processes and microglial activation. Given that intracerebral inflammation and microglial activation play key roles in the mechanism of injury and brain damage in both ischaemic and haemorrhagic stroke, we have investigated the potential beneficial actions of Ang-(1-7) in stroke-prone spontaneously hypertensive rats (spSHRs), an established animal model of hypertension-induced haemorrhagic stroke. Angiotensin-(1-7) was administered by continuous infusion via the intracerebroventricular route for 6 weeks into spSHRs fed a high-sodium (4%) diet, starting at 49 days of age. This treatment resulted in a significant increase in survival of the spSHRs. Median survival was 108 days in control, artificial cerebrospinal fluid-infused spSHRs and 154 days in Ang-(1-7)-treated spSHRs. This effect was partly reversed by intracerebroventricular infusion of the Mas receptor blocker, A779. This Ang-(1-7) treatment also decreased the number of haemorrhages in the striatum, improved neurological status (reduced lethargy), decreased the number of microglia in the striatum and tended to increase neuron survival at the same site. Importantly, infusions of Ang-(1-7) had no effect on kidney pathology, heart pathology, body weight, serum corticosterone levels or blood pressure. This study is the first to demonstrate the cerebroprotective actions of Ang-(1-7), including increased survival time, in spSHRs. As such, these data reveal a potential therapeutic target for haemorrhagic stroke.


Asunto(s)
Angiotensina I/farmacología , Hipertensión/complicaciones , Fragmentos de Péptidos/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/mortalidad , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Corticosterona/sangre , Corazón/efectos de los fármacos , Infusiones Intraventriculares , Riñón/efectos de los fármacos , Masculino , Microglía/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Accidente Cerebrovascular/sangre
14.
Neuropharmacology ; 71: 154-63, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23583926

RESUMEN

Previously we demonstrated that central administration of angiotensin-(1-7) [Ang-(1-7)] into rats elicits significant cerebroprotection against ischemic stroke elicited by endothelin-1 induced middle cerebral artery occlusion. Ang-(1-7), acting via its receptor Mas, reduced cerebral infarct size, and rats exhibited improved performance on neurological exams. These beneficial actions of Ang-(1-7) were not due to inhibition of the effects of endothelin-1 on cerebral vasoconstriction or effects on cerebral blood flow, and so we considered other potential mechanisms. Here we investigated the possibility that the Ang-(1-7)-induced cerebroprotection involves an anti-inflammatory effect, since stroke-induced cerebral damage includes an excessive intracerebral inflammatory response. Our quantitative RT-PCR analyses revealed that central Ang-(1-7) treatment attenuates the increased expression of mRNAs for inducible nitric oxide synthase (iNOS), several pro-inflammatory cytokines and cluster of differentiation molecule 11b (microglial marker) within the cerebral cortex following endothelin-1 induced stroke. Western blotting confirmed similar changes in iNOS protein expression in the cerebral cortex. In support of these observations, immunostaining revealed the presence of immunoreactive Mas on activated microglia within the cerebral cortical infarct zone, and in vitro experiments demonstrated that lipopolysaccharide-induced increases in nitric oxide production in glial cultures are attenuated by Ang-(1-7) acting via Mas. Collectively these findings demonstrate an anti-inflammatory action of Ang-(1-7) in the brain, and suggest that the cerebroprotective action of this peptide in ischemic stroke may involve effects on nitric oxide generation by microglia.


Asunto(s)
Angiotensina I/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Isquemia Encefálica/fisiopatología , Corteza Cerebral/efectos de los fármacos , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Accidente Cerebrovascular/prevención & control , Angiotensina I/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Isquemia Encefálica/patología , Células Cultivadas , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Ratones Noqueados , Microglía/inmunología , Microglía/metabolismo , Microglía/patología , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Organismos Libres de Patógenos Específicos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismo
15.
J Vis Exp ; (72): e50015, 2013 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-23463164

RESUMEN

Creation of a cranial window is a method that allows direct visualization of structures on the cortical surface of the brain(1-3). This technique can be performed in many locations overlying the rat cerebrum, but is most easily carried out by creating a craniectomy over the readily accessible frontal or parietal bones. Most frequently, we have used this technique in combination with the endothelin-1 middle cerebral artery occlusion model of ischemic stroke to quantify the changes in middle cerebral artery vessel diameter that occur with injection of endothelin-1 into the brain parenchyma adjacent to the proximal MCA(4, 5). In order to visualize the proximal portion of the MCA during endothelin -1 induced MCAO, we use a technique to create a cranial window through the temporal bone on the lateral aspect of the rat skull (Figure 1). Cerebral arteries can be visualized either with the dura intact or with the dura incised and retracted. Most commonly, we leave the dura intact during visualization since endothelin-1 induced MCAO involves delivery of the vasoconstricting peptide into the brain parenchyma. This bypasses the need to incise the dura directly over the visualized vessels for drug delivery. This protocol will describe how to create a cranial window to visualize cerebral arteries in a step-wise fashion, as well as how to avoid many of the potential pitfalls pertaining to this method.


Asunto(s)
Endotelina-1/administración & dosificación , Infarto de la Arteria Cerebral Media/inducido químicamente , Arteria Cerebral Media/efectos de los fármacos , Arteria Cerebral Media/cirugía , Cráneo/cirugía , Animales , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratas , Ratas Sprague-Dawley
16.
J Vis Exp ; (72)2013 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-23438950

RESUMEN

Stroke is the number one cause of disability and third leading cause of death in the world, costing an estimated $70 billion in the United States in 2009. Several models of cerebral ischemia have been developed to mimic the human condition of stroke. It has been suggested that up to 80% of all strokes result from ischemic damage in the middle cerebral artery (MCA) area. In the early 1990s, endothelin-1 (ET-1) was used to induce ischemia by applying it directly adjacent to the surface of the MCA after craniotomy. Later, this model was modified by using a stereotaxic injection of ET-1 adjacent to the MCA to produce focal cerebral ischemia. The main advantages of this model include the ability to perform the procedure quickly, the ability to control artery constriction by altering the dose of ET-1 delivered, no need to manipulate the extracranial vessels supplying blood to the brain as well as gradual reperfusion rates that more closely mimics the reperfusion in humans. On the other hand, the ET-1 model has disadvantages that include the need for a craniotomy, as well as higher variability in stroke volume. This variability can be reduced with the use of laser Doppler flowmetry (LDF) to verify cerebral ischemia during ET-1 infusion. Factors that affect stroke variability include precision of infusion and the batch of the ET-1 used. Another important consideration is that although reperfusion is a common occurrence in human stroke, the duration of occlusion for ET-1 induced MCAO may not closely mimic that of human stroke where many patients have partial reperfusion over a period of hours to days following occlusion. This protocol will describe in detail the ET-1 induced MCAO model for ischemic stroke in rats. It will also draw attention to special considerations and potential drawbacks throughout the procedure.


Asunto(s)
Modelos Animales de Enfermedad , Endotelina-1/administración & dosificación , Infarto de la Arteria Cerebral Media/inducido químicamente , Flujometría por Láser-Doppler/métodos , Accidente Cerebrovascular/inducido químicamente , Animales , Masculino , Arteria Cerebral Media/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
17.
Exp Physiol ; 96(10): 1084-96, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21685445

RESUMEN

Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin-(1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang-(1-7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang-(1-7) and DIZE were reversed by co-intracerebroventricular administration of the Mas receptor inhibitor, A-779. Neither the Ang-(1-7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET-1. Lastly, intracerebroventricular administration of Ang-(1-7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET-1-induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2-Ang-(1-7)-Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang-(1-7) protective action includes blunting of inducible nitric oxide synthase expression.


Asunto(s)
Angiotensina I/uso terapéutico , Infarto de la Arteria Cerebral Media/inducido químicamente , Fragmentos de Péptidos/uso terapéutico , Accidente Cerebrovascular/prevención & control , Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Animales , Diminazeno/análogos & derivados , Diminazeno/farmacología , Endotelina-1 , Activación Enzimática , Masculino , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Fragmentos de Péptidos/farmacología , Peptidil-Dipeptidasa A/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/fisiología
18.
Amino Acids ; 40(4): 1151-8, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20839013

RESUMEN

The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.


Asunto(s)
Epilepsia/tratamiento farmacológico , Hidrocarburos Bromados/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Tirosina/análogos & derivados , Animales , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Caspasa 3/análisis , Modelos Animales de Enfermedad , Endotelina-1/efectos adversos , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hidrocarburos Bromados/administración & dosificación , Hidrocarburos Bromados/síntesis química , Infarto de la Arteria Cerebral Media/inducido químicamente , Masculino , Actividad Motora/efectos de los fármacos , Pentilenotetrazol/efectos adversos , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/fisiopatología , Tirosina/administración & dosificación , Tirosina/síntesis química , Tirosina/uso terapéutico
20.
Exp Physiol ; 94(8): 937-46, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19429641

RESUMEN

Endogenous levels of angiotensin II (Ang II) are increased in the cortex and hypothalamus following stroke, and Ang II type 1 receptor blockers (ARBs) have been shown to attenuate the deleterious effects in animal stroke models using middle cerebral artery (MCA) intraluminal occlusion procedures. However, the endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO) model of cerebral ischaemia is thought to more closely mimic the temporal events of an embolic stroke. This method provides rapid occlusion of the MCA and a gradual reperfusion that lasts for 16-22 h. The aim of the present study was to evaluate whether systemic administration of an ARB prior to ET-1-induced MCAO would provide cerebroprotection during this model of ischaemic stroke. Injection of 3 microl of 80 microM ET-1 adjacent to the MCA resulted in complete occlusion of the vessel that resolved over a period of 30-40 min. Following ET-1-inducedMCAO, rats had significant neurological impairment, as well as an infarct that consisted of 30% of the ipsilateral grey matter. Systemic pretreatment with 0.2 mg kg(-1) day(-1) candesartan for 7 days attenuated both the infarct size and the neurological deficits caused by ET-1-induced MCAO without altering blood pressure. This study confirms the cerebroprotective properties of ARBs during ischaemic stroke and validates the ET-1-induced MCAO model for examination of the role of the brain renin-angiotensin system in ischaemic stroke.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Infarto de la Arteria Cerebral Media/fisiopatología , Tetrazoles/farmacología , Animales , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/prevención & control , Infarto Cerebral/prevención & control , Modelos Animales de Enfermedad , Endotelina-1 , Infarto de la Arteria Cerebral Media/inducido químicamente , Masculino , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/prevención & control
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