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1.
Hypertension ; 74(4): 1041-1051, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476904

RESUMO

Transient hypertension is a risk factor for Alzheimer disease (AD), but the effects of this interaction on brain vasculature are understudied. Addressing vascular pathology is a promising avenue to potentiate the efficacy of treatments for AD. We used arterial spin labeling magnetic resonance imaging to longitudinally assess brain vascular function and immunohistopathology to examine cerebrovascular remodeling and amyloid load. Hypertension was induced for 1 month by administration of l-NG-nitroarginine-methyl-ester in TgF344-AD rats at the prodromal stage. Following hypertension, nontransgenic rats showed transient cerebrovascular changes, whereas TgF344-AD animals exhibited sustained alterations in cerebrovascular function. Human umbilical cord perivascular cells in combination with scyllo-inositol, an inhibitor of Aß oligomerization, resulted in normalization of hippocampal vascular function and remodeling, in contrast to either treatment alone. Prodromal stage hypertension exacerbates latter AD pathology, and the combination of human umbilical cord perivascular cells with amyloid clearance promotes cerebrovascular functional recovery.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipertensão/fisiopatologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Hemodinâmica/fisiologia , Hipertensão/complicações , Hipertensão/terapia , Imagem por Ressonância Magnética , Ratos , Marcadores de Spin
2.
Neuroscience ; 371: 166-177, 2018 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-29229555

RESUMO

To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO2 challenges in both the hippocampus and the neocortex. CAF rats switched to chow for one month (SWT) exhibited improved resting perfusion in the hippocampus as well as improved cerebrovascular reactivity in the neocortex. However, the diet switch did not correct cerebrovascular reactivity in the hippocampus. These changes were not accompanied by alterations in the structural integrity of the cerebral microvasculature, examined using rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) immunostaining. Also, the extent of tissue damage induced by endothelin-1 injection into sensorimotor cortex was not affected by the Cafeteria diet. These results demonstrate that short-term consumption of an ultra-processed diet reduces cerebrovascular reactivity. This effect persists after dietary normalization despite recovery of peripheral symptomatology.


Assuntos
Circulação Cerebrovascular/fisiologia , Dieta Ocidental/efeitos adversos , Hemodinâmica/fisiologia , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Endotelina-1 , Hipocampo/irrigação sanguínea , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Síndrome Metabólica/diagnóstico por imagem , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
3.
J Magn Reson Imaging ; 46(2): 505-517, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28703413

RESUMO

PURPOSE: Stroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stage-that most patients stand to benefit from-reflects uncertainty surrounding mechanisms that govern recovery. The present work investigated the effects of a novel treatment (selective cyclooxygenase-1, COX-1, inhibition) in a model of focal ischemia. MATERIALS AND METHODS: FR122047 (COX-1 inhibitor) was given beginning 7 days following stroke (cortical microinjection of endothelin-1) in 23 adult male rats. Longitudinal continuous-arterial-spin-labeling was performed prior to treatment (7 days), and repeated following treatment (21 days) on a 7T magnetic resonance imaging (MRI) system to estimate resting perfusion and reactivity to hypercapnia. These in vivo measurements were buttressed by immunohistochemistry. RESULTS: Stroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 170 ± 10%) and perfusion responses to hypercapnia (180 ± 10%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (100 ± 20%) but persistent hyperreactivity (190 ± 20%). Treated animals exhibited sustained perilesional hyperperfusion (180 ± 10%). Further, reactivity lateralization did not persist following treatment (peri- vs. contralesional reactivity: P = 0.002 at 7 vs. P = 0.2 at 21 days). Hemodynamic changes were accompanied by neuronal loss, increased endothelial density, and widespread microglial and astrocytic activation. Moreover, relative to controls, treated rats showed increased perilesional neuronal survival (22 ± 1% vs. 14.9 ± 0.8%, P = 0.02) and decreased microglia/macrophage recruitment (17 ± 1% vs. 20 ± 1%, P = 0.05). Finally, perilesional perfusion was correlated with neuronal survival (slope = 0.14 ± 0.05; R2 = 0.7, P = 0.03). CONCLUSION: These findings shed light on the role of COX-1 in chronic ischemic injury and suggest that delayed selective COX-1 inhibition exerts multiple beneficial effects on the neurogliovascular unit. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Isquemia/diagnóstico por imagem , Imagem por Ressonância Magnética , Proteínas de Membrana/antagonistas & inibidores , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Animais , Ciclo-Oxigenase 1 , Modelos Animais de Doenças , Endotelina-1/química , Macrófagos/patologia , Masculino , Microglia/patologia , Neuroglia/patologia , Neurônios/patologia , Perfusão , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Marcadores de Spin , Tiazóis/química
4.
Sci Rep ; 7: 46427, 2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28401931

RESUMO

Alzheimer's disease (AD), pathologically characterized by amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aß-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Rede Nervosa/fisiopatologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Rede Nervosa/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Ratos , Ratos Transgênicos , Proteínas tau/metabolismo
5.
J Cereb Blood Flow Metab ; 37(3): 1046-1059, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27683451

RESUMO

Aerobic activity has been shown highly beneficial to brain health, yet much uncertainty still surrounds the effects of exercise on the functioning of cerebral microvasculature. This study used two-photon fluorescence microscopy to examine cerebral hemodynamic alterations as well as accompanying geometric changes in the cortical microvascular network following five weeks of voluntary exercise in transgenic mice endogenously expressing tdTomato in vascular endothelial cells to allow visualization of microvessels irrespective of their perfusion levels. We found a diminished microvascular response to a hypercapnic challenge (10% FiCO2) in running mice when compared to that in nonrunning controls despite commensurate increases in transcutaneous CO2 tension. The flow increase to hypercapnia in runners was 70% lower than that in nonrunners (p = 0.0070) and the runners' arteriolar red blood cell speed changed by only half the amount seen in nonrunners (p = 0.0085). No changes were seen in resting hemodynamics or in the systemic physiological parameters measured. Although a few unperfused new vessels were observed on visual inspection, running did not produce significant morphological differences in the microvascular morphometric parameters, quantified following semiautomated tracking of the microvascular networks. We propose that voluntary running led to increased cortical microvascular efficiency and desensitization to CO2 elevation.


Assuntos
Córtex Cerebral/irrigação sanguínea , Condicionamento Físico Animal/fisiologia , Animais , Circulação Cerebrovascular , Hemodinâmica , Hipercapnia/fisiopatologia , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Corrida/fisiologia
6.
Neuroimage ; 146: 869-882, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27664828

RESUMO

Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm3 or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia and macrophages, with neuronal loss and inflammation extending beyond the peri-lesional cortex. These findings highlight the complex relationship between neurophysiological state and behaviour and provide evidence of highly dynamic functional changes in the peri-infarct zone weeks following the ischemic insult, suggesting an extended temporal window for therapeutic interventions.


Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Córtex Somatossensorial/irrigação sanguínea , Córtex Somatossensorial/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Remodelação Vascular , Animais , Encéfalo/metabolismo , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Ondas Encefálicas , Encefalite/complicações , Encefalite/metabolismo , Endotelina-1/administração & dosagem , Hipercapnia/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Destreza Motora , Neuroglia/metabolismo , Neurônios/metabolismo , Estimulação Física , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Córtex Sensório-Motor/efeitos dos fármacos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/complicações , Percepção do Tato/fisiologia
7.
Physiol Behav ; 167: 382-391, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27705750

RESUMO

Many promising findings from pre-clinical research have failed to translate to the clinic due to their inability to incorporate human disease co-morbidity. A variety of rodent diets and feeding durations are currently used in models of human metabolic syndrome, obesity and diabetes. One model, the Cafeteria (CAF) diet, makes use of grocery store-purchased food items that more closely approximate the human ultra-processed diet than commercial high-fat or high-sugar rodent diets. The present study describes the development of metabolic syndrome in rats fed a CAF diet as well as the recovery of metabolic syndrome following a healthy "lifestyle" change. In addition, we explored the effects of CAF diet on spatial learning and memory and on neuroinflammation. Three-week old male Sprague-Dawley rats were fed a CAF diet for three months that consisted of 16 highly palatable human food items along with standard chow and a 12% sucrose solution to mimic soda consumption. Thereafter, a sub-group of CAF diet rats was switched to a chow diet (SWT) for one month. Both CAF and SWT groups were compared to control rats maintained on a standard chow diet (SD). Prior to the diet switch, CAF and SWT animals developed features akin to metabolic syndrome. Both groups of rats displayed significant abdominal obesity with increased visceral adiposity, hyperinsulinemia, glucose intolerance and dyslipidemia with elevated serum triglyceride levels and reduced HDL cholesterol. Switching to a chow diet for one month completely reversed these features in SWT animals. Although acquisition of the Barnes maze was not affected by the CAF diet, these animals exhibited greater hippocampal neuroinflammation compared to both SD and SWT rats as assessed by Iba1 staining. These results demonstrate that the CAF diet is very effective in creating metabolic syndrome with hippocampal inflammation in rats over a relatively short time span. This model may be of great heuristic importance in determining potential reversibility of metabolic and cerebrovascular pathologies across the lifespan and as a co-morbid factor in other disease models such as stroke.


Assuntos
Dieta/efeitos adversos , Doenças Metabólicas/fisiopatologia , Análise de Variância , Animais , Peso Corporal , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Ingestão de Energia , Teste de Tolerância a Glucose , Gordura Intra-Abdominal/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico por imagem , Proteínas dos Microfilamentos/metabolismo , Ratos , Ratos Sprague-Dawley , Gordura Subcutânea/diagnóstico por imagem
8.
PLoS One ; 11(10): e0165393, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27768761

RESUMO

Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer's disease (AD)-like pathology, specifically Aß-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Aß pathology with scyllo-inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of scyllo-inositol treatment. The prolonged exposure to Aß-pathology leads to deficits in the neurogenic niche, thus targeting Aß alone is insufficient to rescue neurogenesis. To support the neurogenic niche, we combined scyllo-inositol treatment with leteprinim potassium (neotrofin), the latter of which stimulates neurotrophin expression. We show that the combination treatment of scyllo-inositol and neotrofin enhances neuronal survival and differentiation. We propose this proof of concept combination therapy of targeting Aß-pathology and neurotrophin deficits as a potential treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Modelos Animais de Doenças , Fatores de Crescimento Neural/uso terapêutico , Neurogênese , Doença de Alzheimer/patologia , Animais , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos
9.
Biochim Biophys Acta ; 1862(5): 957-65, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26521151

RESUMO

Despite the growing recognition of the significance of cerebrovascular impairment in the etiology and progression of Alzheimer's disease (AD), the early stage brain vascular dysfunction and its sensitivity to pharmacological interventions is still not fully characterized. Due to the early and aggressive treatment of probable AD with cholinesterase inhibitors (ChEI), which in and of themselves have direct effects on brain vasculature, the vast majority of hemodynamic measurements in early AD subjects reported hitherto have consequently been made only after the start of treatment, complicating the disentanglement of disease- vs. treatment-related effects on the cerebral vasculature. To address this gap, we used pseudo continuous arterial spin labeling MRI to measure resting perfusion and visual stimulation elicited changes in cerebral blood flow (CBF) and blood oxygenation dependent (BOLD) fMRI signal in a cohort of mild AD patients immediately prior to, 6months post, and 12months post commencement of open label cholinesterase inhibitor treatment. Although patients exhibited no gray matter atrophy prior to treatment and their resting perfusion was not distinguishable from that in age, education and gender-matched controls, the patients' visual stimulation-elicited changes in BOLD fMRI and blood flow were decreased by 10±4% (BOLD) and 23±2% (CBF), relative to those in controls. Induction of cholinesterase inhibition treatment was associated with a further, 7±2% reduction in patients' CBF response to visual stimulation, but it stabilized, at this new lower level, over the follow-up period. Likewise, MMSE scores remained stable during the treatment; furthermore, higher MMSE scores were associated with higher perfusion responses to visual stimulation. This study represents the initial step in disentangling the effects of AD pathology from those of the first line treatment with cholinesterase inhibitors on cerebral hemodynamics and supports the use of arterial spin labeling MRI for quantitative evaluation of the brain vascular function in mild Alzheimer's disease. The findings provide evidence of a pronounced deficit in the visual cortex hyperemia despite the relative sparing of visual function in early stage AD, its reduction with ChEI treatment induction, and its stabilization in the first year of cholinesterase inhibition treatment. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.


Assuntos
Doença de Alzheimer/terapia , Circulação Cerebrovascular , Inibidores da Colinesterase/uso terapêutico , Hiperemia/terapia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Coortes , Feminino , Humanos , Hiperemia/sangue , Hiperemia/diagnóstico por imagem , Hiperemia/patologia , Imagem por Ressonância Magnética , Masculino , Estimulação Luminosa
10.
Neuroimage ; 125: 988-995, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26577887

RESUMO

The gut microbiome has been shown to regulate the development and functions of the enteric and central nervous systems. Its involvement in the regulation of behavior has attracted particular attention because of its potential translational importance in clinical disorders, however little is known about the pathways involved. We previously have demonstrated that administration of Lactobacillus rhamnosus (JB-1) to healthy male BALB/c mice, promotes consistent changes in GABA-A and -B receptor sub-types in specific brain regions, accompanied by reductions in anxiety and depression-related behaviors. In the present study, using magnetic resonance spectroscopy (MRS), we quantitatively assessed two clinically validated biomarkers of brain activity and function, glutamate+glutamine (Glx) and total N-acetyl aspartate+N-acetyl aspartyl glutamic acid (tNAA), as well as GABA, the chief brain inhibitory neurotransmitter. Mice received 1×10(9) cfu of JB-1 per day for 4weeks and were subjected to MRS weekly and again 4weeks after cessation of treatment to ascertain temporal changes in these neurometabolites. Baseline concentrations for Glx, tNAA and GABA were equal to 10.4±0.3mM, 8.7±0.1mM, and 1.2±0.1mM, respectively. Delayed increases were first seen for Glx (~10%) and NAA (~37%) at 2weeks which persisted only to the end of treatment. However, Glx was still elevated 4weeks after treatment had ceased. Significantly elevated GABA (~25%) was only seen at 4weeks. These results suggest specific metabolic pathways in our pursuit of mechanisms of action of psychoactive bacteria. They also offer through application of standard clinical neurodiagnostic techniques, translational opportunities to assess biomarkers accompanying behavioral changes induced by alterations in the gut microbiome.


Assuntos
Ácido Aspártico/análogos & derivados , Encéfalo/metabolismo , Ácido Glutâmico/biossíntese , Lactobacillus rhamnosus , Probióticos/farmacologia , Ácido gama-Aminobutírico/biossíntese , Animais , Ácido Aspártico/análise , Ácido Aspártico/biossíntese , Química Encefálica/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Microbioma Gastrointestinal/fisiologia , Ácido Glutâmico/análise , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ácido gama-Aminobutírico/análise
11.
J Cereb Blood Flow Metab ; 35(10): 1601-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25966952

RESUMO

To aid in development of chronic stage treatments for sensorimotor deficits induced by ischemic stroke, we investigated the effects of GABA antagonism on brain structure and fine skilled reaching in a rat model of focal ischemia induced via cortical microinjections of endothelin-1 (ET-1). Beginning 7 days after stroke, animals were administered a gamma-aminobutyric acid (GABAA) inverse agonist, L-655,708, at a dose low enough to afford α5-GABAA receptor specificity. A week after stroke, the ischemic lesion comprised a small hypointense necrotic core (6±1 mm(3)) surrounded by a large (62±11 mm(3)) hyperintense perilesional region; the skilled reaching ability on the Montoya staircase test was decreased to 34%±2% of the animals' prestroke performance level. On L-655,708 treatment, animals showed a progressive decrease in total stroke volume (13±4 mm(3) per week), with no change in animals receiving placebo. Concomitantly, treated animals' skilled reaching progressively improved by 9%±1% per week, so that after 2 weeks of treatment, these animals performed at 65%±6% of their baseline ability, which was 25%±11% better than animals given placebo. These data indicate beneficial effects of delayed, sustained low-dose GABAA antagonism on neuroanatomic injury and skilled reaching in the chronic stage of stroke recovery in an ET-1 rat model of focal ischemia.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/psicologia , Destreza Motora/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Endotelina-1/farmacologia , Antagonistas GABAérgicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Necrose , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Taxa Respiratória/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos
12.
Brain ; 138(Pt 4): 1046-58, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25688079

RESUMO

Most patients with Alzheimer's disease exhibit accumulation of amyloid-ß peptide on leptomeningeal and cortical arterioles, or cerebral amyloid angiopathy, which is associated with impaired vascular reactivity and accelerated cognitive decline. Despite widespread recognition of the significance of vascular dysfunction in Alzheimer's disease aetiology and progression, much uncertainty still surrounds the mechanism underlying Alzheimer's disease vascular injury. Studies to date have focused on amyloid-ß-induced damage to capillaries and plaque-associated arterioles, without examining effects across the entire vascular bed. In the present study, we investigated the structural and functional impairment of the feeding arteriolar versus draining venular vessels in a transgenic murine Alzheimer's disease model, with a particular focus on the mural cell populations that dictate these vessels' contractility. Although amyloid-ß deposition was restricted to arterioles, we found that vascular impairment extended to the venules, which showed significant depletion of their mural cell coverage by the mid-stage of Alzheimer's disease pathophysiology. These structural abnormalities were accompanied by an abolishment of the normal vascular network flow response to hypercapnia: this functional impairment was so severe as to result in hypercapnia-induced flow decreases in the arterioles. Further pharmacological depletion of mural cells using SU6668, a platelet-derived growth factor receptor-ß antagonist, resulted in profound structural abnormalities of the cortical microvasculature, including vessel coiling and short-range looping, increased tortuosity of the venules but not of the arterioles, increased amyloid-ß deposition on the arterioles, and further alterations of the microvascular network cerebral blood flow response to hypercapnia. Together, this work shows hitherto unrecognized structural alterations in penetrating venules, demonstrates their functional significance and sheds light on the complexity of the relationship between vascular network structure and function in Alzheimer's disease.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Vênulas/patologia , Vênulas/fisiopatologia , Animais , Cricetinae , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica/métodos
13.
Eur J Neurosci ; 37(12): 1994-2004, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23773069

RESUMO

The inter-relationship between vascular dysfunction and Alzheimer's disease pathology is not clearly understood; however, it is clear that the accumulation of amyloid-beta peptide and loss of vascular function contribute to the cognitive decline detected in patients. At present, imaging modalities can monitor the downstream effects of vascular dysfunction such as cerebral blood flow alterations, white and gray matter lacunes, and ischemic lesions; however, they cannot distinguish parenchymal plaques from cerebrovascular amyloid. Much of our understanding regarding the relationship between amyloid and vascular dysfunction has come from longitudinal population studies and mouse models. In this review, we will discuss the breadth of data generated on vascular function in mouse models of Alzheimer's disease and cerebrovascular amyloid angiopathy. We will also discuss therapeutic strategies targeting the reduction of cerebrovascular amyloid angiopathy and improvement of vascular function.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/metabolismo , Cérebro/irrigação sanguínea , Cérebro/patologia , Doença de Alzheimer/patologia , Animais , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Inositol/uso terapêutico , Camundongos , Sinvastatina/uso terapêutico
14.
FEBS Lett ; 587(15): 2448-54, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-23792157

RESUMO

To identify potential biomarkers associated with Alzheimer's disease (AD)-like neuropathologies in the murine brain, we conducted proteomic analyses of neocortices from TgCRND8 mice. Here we found that phosphoprotein enriched in astrocytes 15 kDa (PEA-15) is expressed at higher levels in the neocortical proteomes from 6-month old TgCRND8 mice, as compared to non-transgenic mice. Immunostaining for PEA-15 revealed reactive astrocytes associated with the neocortical amyloid plaques in TgCRND8 mice and in post-mortem human AD brains. This is the first report of increased phosphoprotein enriched in astrocytes (PEA-15) expression in reactive astrocytes of an AD mouse model and human AD brains.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Astrócitos/fisiologia , Encéfalo/metabolismo , Fosfoproteínas/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Humanos , Camundongos , Camundongos Transgênicos
15.
Adv Pharmacol ; 64: 177-212, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22840748

RESUMO

Preclinical development of scyllo-inositol for the treatment of Alzheimer's disease (AD) has been investigated in both in vitro and in vivo models with positive results. scyllo-Inositol stabilized a small conformer of Aß42 in vitro, neutralized cell derived Aß trimers and promoted low molecular weight Aß species in vivo. These interactions resulted in decreased neuronal toxicity, increased long-term potentiation (LTP) and ablation of cognitive deficits in multiple mouse models of AD. scyllo-Inositol bioavailability, pharmacokinetics, and small animal toxicology studies demonstrated the potential for translation to human patients. The results of Phase I and Phase II clinical trials for AD are presented. Furthermore, the use of this compound for imaging and other amyloid related disorders is discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ensaios Clínicos como Assunto , Inositol/uso terapêutico , Doença de Alzheimer/patologia , Animais , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos , Humanos , Inositol/farmacocinética , Relação Estrutura-Atividade
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