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Serum amyloid A (SAA) proteins increase dramatically in the blood following inflammation. Recently, SAAs are increased in humans following stroke and in ischemic animal models. However, the impact of SAAs on whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of SAA and SAA signaling in the ischemic brain. Wildtype and SAA deficient mice were exposed to middle cerebral artery occlusion and reperfusion, examined for the impact of infarct volumes, behavioral changes, inflammatory markers, TUNEL staining, and BBB changes. The underlying mechanisms were investigated using SAA deficient mice, transgenic mice and viral vectors. SAA levels were significantly increase following MCAo and mice deficient in SAAs showed reduced infarct volumes and improved behavioral outcomes. SAA deficient mice showed a reduction in TUNEL staining, inflammation and decreased glial activation. Mice lacking acute phase SAAs demonstrated a reduction in expression of the NLRP3 inflammasome and SAA/NLRP3 KO mice showed improvement. Restoration of SAA expression via SAA tg mice or adenoviral expression reestablished the detrimental effects of SAA. A reduction in BBB permeability was seen in the SAA KO mice and anti-SAA antibody treatment reduced the effects on ischemic injury. SAA signaling plays a critical role in regulating NLRP3-induced inflammation and glial activation in the ischemic brain. Blocking this signal will be a promising approach for treating ischemic stroke.
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Introduction: Various lifestyle factors such as chronic hypertension and a high-sodium diet regimen are shown to impact cerebrovascular morphology and structure. Unusual cerebrovascular morphological and structural changes may contribute to cerebral hypoperfusion in Alzheimer's disease (AD). The objective of this study was to examine whether a high-sodium diet mediates cerebrovascular morphology and cerebral perfusion alterations in AD. Methods: Double transgenic mice harboring Aß precursor protein (APPswe) and presenilin-1 (PSEN1) along with wild-type controls were divided into four groups. Group A (APP/PS1) and B (controls) were both fed a high-sodium (4.00%), while group C (APP/PS1) and D (controls) were both fed a low-sodium (0.08% a regular chow diet) for three months. Then, changes in regional cerebral perfusion and diffusion, cerebrovascular morphology, and structure were quantified. Results: A 3-month high-sodium diet causes pyknosis and deep staining in hippocampal neurons and reduced vascular density in both hippocampal and cortical areas (p <0.001) of APP/PS1. Despite vascular density changes, cerebral perfusion was not increased markedly (p = 0.3) in this group, though it was increased more in wild-type controls (p = 0.022). Conclusion: A high-sodium diet regimen causes cerebrovascular morphology alteration in APP/PS1 mouse model of AD.
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Plant-based nutritional supplementation has been shown to attenuate and reduce mortality in the processes of both acute and chronic disorders, including diabetes, obesity, cardiovascular disease, cancer, inflammatory diseases, and neurological and neurodegenerative disorders. Low-level systemic inflammation is an important contributor to these afflictions and diets enriched in phytochemicals can slow the progression. The goal of this study was to determine the impact of lipopolysaccharide (LPS)-induced inflammation on changes in glucose and insulin tolerance, performance enhancement, levels of urinary neopterin and concentrations of neurotransmitters in the striatum in mouse models. Both acute and chronic injections of LPS (2 mg/kg or 0.33 mg/kg/day, respectively) reduced glucose and insulin tolerance and elevated neopterin levels, which are indicative of systemic inflammatory responses. In addition, there were significant decreases in striatal neurotransmitter levels (dopamine and DOPAC), while serotonin (5-HT) levels were essentially unchanged. LPS resulted in impaired execution in the incremental loading test, which was reversed in mice on a supplemental plant-based diet, improving their immune function and maintaining skeletal muscle mitochondrial activity. In conclusion, plant-based nutritional supplementation attenuated the metabolic changes elicited by LPS injections, causing systemic inflammatory activity that contributed to both systemic and neurological alterations.
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Inflamación/dietoterapia , Músculo Esquelético/metabolismo , Obesidad/dietoterapia , Fitoquímicos/farmacología , Animales , Dieta , Suplementos Dietéticos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Glucosa/metabolismo , Inflamación/inducido químicamente , Inflamación/patología , Lipopolisacáridos/toxicidad , Ratones , Músculo Esquelético/efectos de los fármacos , Neopterin/orina , Obesidad/inducido químicamente , Obesidad/patología , Serotonina/metabolismoRESUMEN
Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90 min) followed by 24 h of reperfusion to induce focal I/R injury as an acute stage model. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Furthermore, the role of CYP2E1 on the blood-brain barrier (BBB) integrity was investigated by measuring 20-hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p < 0.005). Moreover, reactive oxygen species (ROS) production, apoptosis, and neurodegeneration were significantly lower in the CYP2E1(-/-) I/R group (p < 0.001). The BBB damage was significantly lower in CYP2E1(-/-) mice compared to wild-type (WT) (p < 0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(-/-) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.
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PURPOSE: To review the recent developments on the effect of chronic high mean arterial blood pressure (MAP) on cerebral blood flow (CBF) autoregulation and supporting the notion that CBF autoregulation impairment has connection with chronic cerebral diseases. Method: A narrative review of all the relevant papers known to the authors was conducted. Results: Our understanding of the connection between cerebral perfusion impairment and chronic high MAP and cerebral disease is rapidly evolving, from cerebral perfusion impairment being the result of cerebral diseases to being the cause of cerebral diseases. We now better understand the intertwined impact of hypertension and Alzheimer's disease (AD) on cerebrovascular sensory elements and recognize cerebrovascular elements that are more vulnerable to these diseases. Conclusion: We conclude with the suggestion that the sensory elements pathology plays important roles in intertwined mechanisms of chronic high MAP and AD that impact cerebral perfusion.
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Enfermedad de Alzheimer/fisiopatología , Presión Arterial/fisiología , Circulación Cerebrovascular , Hipertensión/fisiopatología , Homeostasis , HumanosRESUMEN
Alzheimer's disease (AD) is the result of the deposition of amyloid ß (Aß) peptide into amyloid fibrils and tau into neurofibrillary tangles. At the present time, there are no possible treatments for the disease. We have recently shown that diets enriched in phytonutrients show protection or limit the extent of damage in a number of neurological disorders. GrandFusion (GF) diets have attenuated the outcomes in animal models of traumatic brain injury, cerebral ischemia, and chronic traumatic encephalopathy. In this study, we investigated the effect of GF diets in a mouse model of AD prior to the development of amyloid plaques to show how this treatment paradigm would alter the accumulation of Aß peptide and related pathologic changes (i.e., inflammation, cathepsin B, and memory impairment). Administration of GF diets (2-4%) over a period of four months in APP/ΔPS1 double-transgenic mice resulted in attenuation in Aß peptide levels, reduction of amyloid load, and inflammation, increased cathepsin B expression, and improved spatial orientation. Additionally, treatment with GF diets increased nerve growth factor (NGF) levels in the brain and tempered the memory impairment in the animal model. These data suggest that GF diets may alter the development and progression of the mechanisms associated with the disease process to effectively modify AD pathogenesis.
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Enfermedad de Alzheimer/dietoterapia , Encéfalo/metabolismo , Dieta , Trastornos de la Memoria/dietoterapia , Placa Amiloide/dietoterapia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Ratones , Ratones Transgénicos , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Factores de TiempoRESUMEN
Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1ß (IL-1ß), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1ß induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1ß. N-acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1ß by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes.SIGNIFICANCE STATEMENT In the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1ß release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke.
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Isquemia Encefálica/metabolismo , Inflamasomas/metabolismo , Mediadores de Inflamación/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteína Amiloide A Sérica/toxicidad , Animales , Isquemia Encefálica/patología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/patologíaRESUMEN
The name of author "William Swindell" missed the midle initial "R.". This should be written as "William R. Swindell" as corrected above.
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Alzheimer's disease (AD) results in the deposition of amyloid ß (Aß) peptide into amyloid fibrils and tau into neurofibrillary tangles. Regardless of whether or not these entities are a cause or consequence of the disease process, preventing their accumulation or accelerating their clearance may slow the rate of AD onset. Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a six-amino-acid component of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected the accumulation of Aß peptide and related pathologic changes (e.g., inflammation, nerve growth factor (NGF) expression, cathepsin B, and memory impairment). Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in attenuation in Aß peptide levels, reduction of inflammation and amyloid load, increased cathepsin B expression, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by â¼ 50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways at an early stage to slow the histological and clinical progression of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Oligopéptidos/uso terapéutico , Amiloide/metabolismo , Animales , Astrocitos/patología , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Catepsina B/metabolismo , Humanos , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/patología , Modelos Biológicos , Factores de Crecimiento Nervioso/metabolismo , Presenilina-1/metabolismoRESUMEN
Currently, there are no approved therapeutic drugs for the treatment of traumatic brain injury (TBI), and new targets and approaches are needed to provide relief from the long-term effects of TBI. Recent studies suggest that nutrition plays a critical role in improving the outcome from TBI in both civilians and military personnel. We have previously shown that GrandFusion® (GF) diets improved recovery from cerebral ischemia and enhanced physical activity and endurance in rodent models. We, therefore, sought to determine the impact of a prophylactic diet enriched in fruits and vegetables on recovery from TBI in the controlled cortical impact rodent model. Results demonstrated that mice fed the diets had improved neuromotor function, reduced lesion volume, increased neuronal density in the hippocampus and reduced inflammation. As previously shown, TBI increases cathepsin B as part of the inflammasome complex resulting in elevated inflammatory markers like interleukin-1ß (IL-1ß). Consumption of the GF diets attenuated the increase in cathepsin B levels and prevented the increase in the proapoptotic factor Bax following TBI. These data suggest that prior consumption of diets enriched in fruits and vegetables either naturally or through powdered form can provide protection from the detrimental effects of TBI.
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Lesiones Traumáticas del Encéfalo/complicaciones , Dieta , Frutas , Inflamación/prevención & control , Verduras , Animales , Catepsina B/metabolismo , Inflamación/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Estado Nutricional , Distribución Aleatoria , Recuperación de la FunciónRESUMEN
BACKGROUND: Repetitive mild traumatic brain injuries (rmTBI) are associated with cognitive deficits, inflammation, and stress-related events. We tested the effect of nutrient intake on the impact of rmTBI in an animal model of chronic traumatic encephalopathy (CTE) to study the pathophysiological mechanisms underlying this model. We used a between group design rmTBI closed head injuries in mice, compared to a control and nutrient-treated groups. METHODS: Our model allows for controlled, repetitive closed head impacts to mice. Briefly, 24-week-old mice were divided into five groups: control, rmTBI, and rmTBI with nutrients (2% of NF-216, NF-316 and NF-416). rmTBI mice received four concussive impacts over 7 days. Mice were treated with NutriFusion diets for 2 months prior to the rmTBI and until euthanasia (6 months). Mice were then subsequently euthanized for macro- and micro-histopathologic analysis for various times up to 6 months after the last TBI received. Animals were examined behaviorally, and brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, iba-1 for activated microglia, and AT8 for phosphorylated tau protein. RESULTS: Animals on nutrient diets showed attenuated behavioral changes. The brains from all mice lacked macroscopic tissue damage at all time points. The rmTBI resulted in a marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6 months. Mice treated with diets had significantly reduced inflammation and phospho-tau staining. CONCLUSIONS: The neuropathological findings in the rmTBI mice showed histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation, while mice treated with diets had attenuated disease process. These studies demonstrate that consumption of nutrient-rich diets reduced disease progression.
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Lesiones Traumáticas del Encéfalo/complicaciones , Inflamación/etiología , Inflamación/terapia , Nutrientes/uso terapéutico , Tauopatías/etiología , Tauopatías/terapia , Animales , Síntomas Conductuales/etiología , Síntomas Conductuales/terapia , Lesiones Traumáticas del Encéfalo/terapia , Citocinas/metabolismo , Modelos Animales de Enfermedad , Suspensión Trasera/fisiología , Humanos , Masculino , Ratones , Ratones Transgénicos , Fuerza Muscular/fisiología , Asunción de Riesgos , Sueño/fisiología , Aprendizaje Espacial/fisiología , Natación/psicología , Índices de Gravedad del Trauma , Proteínas tau/genéticaRESUMEN
The consumption of fruits and vegetables appears to help with maintaining an adequate level of exercise and improves endurance. However, the mechanisms that are involved in this process are not well understood. In the current study, the impact of diets enriched in fruits and vegetables (GrandFusion®) on exercise endurance was examined in a mouse model. GrandFusion (GF) diets increased mitochondrial DNA and enzyme activity, while they also stimulated mitochondrial mRNA synthesis in vivo. GF diets increased both the mRNA expression of factors involved in mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), mitochondrial transcription factor A (Tfam), estrogen-related receptor alpha (ERRα), nuclear respiratory factor 1 (NRF-1), cytochrome c oxidase IV (COXIV) and ATP synthase (ATPsyn). Mice treated with GF diets showed an increase in running endurance, rotarod perseverance and grip strength when compared to controls who were on a regular diet. In addition, GF diets increased the protein expression of phosphorylated AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC-1α and peroxisome proliferator-activated receptor delta (PPAR-δ), which was greater than exercise-related changes. Finally, GF reduced the expression of phosphorylated ribosomal protein S6 kinase 1 (p-S6K1) and decreased autophagy. These results demonstrate that GF diets enhance exercise endurance, which is mediated via mitochondrial biogenesis and function.
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Dieta , Estado Nutricional , Resistencia Física , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Peso Corporal , Suplementos Dietéticos , Ingestión de Alimentos , Frutas , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR delta/genética , PPAR delta/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal , Distribución Aleatoria , Sirtuina 1/genética , Sirtuina 1/metabolismo , VerdurasRESUMEN
Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory.
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Disfunción Cognitiva/clasificación , Demencia Vascular/clasificación , Biomarcadores/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Demencia Vascular/diagnóstico por imagen , Demencia Vascular/metabolismo , Demencia Vascular/psicología , HumanosRESUMEN
Physiological and pathological processes that increase or decrease the central nervous system's need for nutrients and oxygen via changes in local blood supply act primarily at the level of the neurovascular unit (NVU). The NVU consists of endothelial cells, associated blood-brain barrier tight junctions, basal lamina, pericytes, and parenchymal cells, including astrocytes, neurons, and interneurons. Knowledge of the NVU is essential for interpretation of central nervous system physiology and pathology as revealed by conventional and advanced imaging techniques. This article reviews current strategies for interrogating the NVU, focusing on vascular permeability, blood volume, and functional imaging, as assessed by ferumoxytol an iron oxide nanoparticle.
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Barrera Hematoencefálica/diagnóstico por imagen , Medios de Contraste , Óxido Ferrosoférrico , Nanopartículas del Metal , Neuroimagen/métodos , Animales , Barrera Hematoencefálica/fisiología , HumanosRESUMEN
Studies have shown that supplementation with extracts from various sources, including fruits and vegetables reverse the age-related changes in movement and cognition. We hypothesized that these beneficial effects result from the presence of anti-oxidants and anti-inflammatory compounds in the fruits and vegetables that contribute to reduced oxidative stress, inflammation and cell death while potentially enhancing neurogenesis. The present study was performed to determine the impact of supplementation with GrandFusion®(GF) to aged Fisher 344 rats for 4 months to determine the impact on attenuation or reversal of the age-related deficits. When the aged rats consumed a diet enriched with the extracts the results showed an improved motor performance, and enhanced cognitive functions. In addition, the rats showed reduced oxidative stress and inflammation, and enhanced neurogenesis, Nrf2 and anti-oxidant expression. The effect of GF extracts on the augmentation of memory and learning is significant and may function through the modulation of antioxidant enzymes, signaling pathways and additional mechanisms to improve the aging process. These studies further support the recommendation of USDA for the consumption of fruits and vegetables to improve healthy aging.
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Envejecimiento/efectos de los fármacos , Frutas , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Extractos Vegetales/farmacología , Verduras , Envejecimiento/psicología , Animales , Femenino , Masculino , Destreza Motora/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas F344RESUMEN
BACKGROUND: Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer's disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear. OBJECTIVE: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-ß (Aßand CBF) and CBF, exacerbates cognitive decline, and increases the propensity to AD. METHODS: Double transgenic mice harboring the amyloid-ß protein precursor (APPswe), and presenilin-1 (PSEN1) along with control littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aß plaques numbers in the cortex and hippocampus of APP/PS1 were quantified. RESULTS: In contrary to controls, APP/PS1 mice fed a high-salt diet did not show markedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p<â0.0001). However, a high-salt diet increased CBF in both APP/PS1 and controls and did not alter the cerebral tissue integrity. Aß plaques were significantly reduced in the cortex and hippocampus of mice fed a high-salt diet. CONCLUSION: These data suggest that a high-salt diet differently affects MAP and CBF in APP/PS1 mice and controls.
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Enfermedad de Alzheimer/fisiopatología , Presión Sanguínea/fisiología , Encéfalo/fisiopatología , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Cloruro de Sodio Dietético/administración & dosificación , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Presión Sanguínea/efectos de los fármacos , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Hipertensión/inducido químicamente , Hipertensión/genética , Hipertensión/fisiopatología , Ratones , Ratones Transgénicos , Presenilina-1/genética , Cloruro de Sodio Dietético/toxicidadRESUMEN
BACKGROUND: Neuroimaging studies in psychostimulant addicts have reported functional neural activity changes in brain regions involved in relapse. However, the difference between the effects of the psychostimulants methamphetamine and cocaine on neuronal activity in a similar setting not been clarified. Since studies in humans are limited by the inability to study the initial impact of psychostimulant drugs, we addressed this issue in a rat model. OBJECTIVE: Here, we report methamphetamine and cocaine-induced blood-oxygen-level dependent (BOLD) signal change using functional magnetic resonance imaging (fMRI) in rats receiving drug for the first time during the imaging session. METHODS: Twenty-three male Long Evans rats underwent fMRI imaging and received an intravenous infusion of methamphetamine, cocaine, or saline. Anatomical and pharmacological fMRI (pfMRI) were performed on a 7T BioSpec dedicated research MR scanner under isoflurane gas (1.5-2%). After collecting baseline data for 10min, rats received drug over the next 10min for a total 40min scan time. Data were then preprocessed and statistically analyzed in anatomically defined regions of interest (ROIs) that have been implicated in persistent drug seeking and relapse. RESULTS: Methamphetamine during the imaging session resulted in a sustained negative BOLD signal change in key regions of the relapse circuit, except for the prefrontal cortex. In contrast, cocaine evoked a positive or unchanged BOLD signal in these same regions. In all of the investigated ROIs, there were no changes in BOLD signal following saline. CONCLUSION: Acute methamphetamine and cocaine have distinct patterns of functional activity as measured by pfMRI.
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Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Metanfetamina/farmacología , Administración Intravenosa , Trastornos Relacionados con Anfetaminas/fisiopatología , Anestésicos por Inhalación/farmacología , Animales , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Trastornos Relacionados con Cocaína/fisiopatología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Isoflurano/farmacología , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangre , Ratas Long-EvansRESUMEN
The pharmacokinetics (PK) of the contrast agent Gd-DTPA administered intravenously (i.v.) for contrast-enhanced MR imaging (DCE-MRI) is an important factor for quantitative data acquisition. We studied the effect of various initial bolus doses on the PK of Gd-DTPA and analyzed population PK of a lower dose for intra-subject variations in DCE-MRI. First, fifteen subjects (23-85years, M/F) were randomly divided into four groups for DCE-MRI with different Gd-DTPA dose: group-I, 0.1mmol/kg, n=4; group-II, 0.05mmol/kg, n=4; group-III, 0.025mmol/kg, n=4; and group-IV, 0.0125mmol/kg, n=3. Sequential fast T1 mapping sequence, after a bolus i.v. Gd-DTPA administered, and a linear T1-[Gd-DTPA] relationship were used to estimate the PK of Gd-DTPA. Secondly, MR-acquired PKs of Gd-DTPA from 58 subjects (28-80years, M/F) were collected retrospectively, from an ongoing study of the brain using DCE-MRI with Gd-DTPA at 0.025mmol/kg, to statistically analyze population PK of Gd-DTPA. We found that the PK of Gd-DTPA (i.v. 0.025mmol/kg) had a half-life of 37.3±6.6min, and was a better fit into a linear T1-[Gd-DTPA] relationship than higher doses (up to 0.1mmol/kg). The area under the curve (AUC) for 0.025mmol/kg was 3.37±0.46, which was a quarter of AUC of 0.1mmol/kg. In population analysis, a dose of 0.025mmol/kg of Gd-DTPA provided less than 5% subject-dependent variation in the PK of Gd-DTPA. Administration of 0.025mmol/kg Gd-DTPA enabled us to estimate [Gd-DTPA] from T1 by using a linear relationship that has a lower estimation error compared to a non-linear relationship. DCE-MRI with a quarter dose of Gd-DTPA is more sensitive to detect changes in [Gd-DTPA].
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Encéfalo/diagnóstico por imagen , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Medios de Contraste/metabolismo , Femenino , Gadolinio DTPA/sangre , Humanos , Masculino , Persona de Mediana Edad , Fantasmas de Imagen , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
OBJECTIVES: Dietary supplementation of fruits and vegetables has been the main stay for nutritional benefit and overall well-being. GrandFusion(®) is a nutritional supplement that contains the natural nutrients from whole fruits and vegetables that include complex nutrients and phytonutrients that contain anti-oxidant, anti-inflammatory, and neuroprotective properties. METHODS: In this study, C57BL/6 mice were fed a diet supplemented with GrandFusion(®) for 2 months prior to 1 hour of ischemia induced by occlusion of the middle cerebral artery (MCAo) followed by various times of reperfusion. Mice were subjected to MCAo for 1 hour and then at various times following reperfusion, animals were assessed for behavioral outcomes (open field testing, rotarod, and adhesive test removal), and infarct volumes (cresyl violet and triphenyltetrazolium chloride). In addition, to determine the potential mechanisms associated with treatment, the brain tissue was examined for changes in oxidative stress and inflammatory markers. RESULTS: The GrandFusion(®) diet was able to show a significant protection from infarct damage in the brain and an improvement in neurological outcomes. The diet did not alter heart rate, blood pressure, pO2, pCO2, or pH. In addition, the diet mitigated inflammation by reducing microglial and astrocytic activation following ischemia and reperfusion and limiting oxidative stress. DISCUSSION: The study demonstrates the neuroprotective effect of a diet rich in fruits and vegetables that contain anti-oxidant and anti-inflammatory against the impact of cerebral ischemia and reperfusion injury.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Isquemia Encefálica/fisiopatología , Corteza Cerebral/irrigación sanguínea , Suplementos Dietéticos , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Antioxidantes/uso terapéutico , Astrocitos/inmunología , Astrocitos/metabolismo , Astrocitos/patología , Conducta Animal , Biomarcadores/metabolismo , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Circulación Cerebrovascular , Frutas/química , Mediadores de Inflamación/metabolismo , Ratones Endogámicos C57BL , Microglía/inmunología , Microglía/metabolismo , Microglía/patología , Estrés Oxidativo , Distribución Aleatoria , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Análisis de Supervivencia , Verduras/químicaRESUMEN
The locus coeruleus (LC) noradrenergic system regulates arousal and modulates attention through its extensive projections across the brain. LC dysfunction has been implicated in a broad range of neurodevelopmental, neurodegenerative and psychiatric disorders, as well as in the cognitive changes observed during normal aging. Magnetic resonance imaging (MRI) has been used to characterize the human LC (elevated contrast relative to surrounding structures), but there is limited understanding of the factors underlying putative LC contrast that are critical to successful biomarker development and confidence in localizing nucleus LC. We used ultra-high-field 7 T magnetic resonance imaging (MRI) to acquire T1-weighted microscopy resolution images (78 µm in-plane resolution) of the LC from post-mortem tissue samples. Histological analyses were performed to characterize the distribution of tyrosine hydroxylase (TH) and neuromelanin in the scanned tissue, which allowed for direct comparison with MR microscopy images. Our results indicate that LC-MRI contrast corresponds to the location of neuromelanin cells in LC; these also correspond to norepinephrine neurons. Thus, neuromelanin appears to serve as a natural contrast agent for nucleus LC that can be used to localize nucleus LC and may have the potential to characterize neurodegenerative disease.