Dietary nitrate supplementation and cognitive health: the nitric oxide-dependent neurovascular coupling hypothesis.

Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial.

Impairment of neurovascular coupling in the hippocampus due to decreased nitric oxide bioavailability supports early cognitive dysfunction in type 2 diabetic rats.

Numerous epidemiological and preclinical studies have established a strong correlation between type 2 diabetes (T2DM) and cognitive impairment and T2DM is now established as an undisputable risk factor in different forms of dementia. However, the mechanisms underlying cognitive impairment in T2DM are still not fully understood. The temporal and spatial coupling between neuronal activity and cerebral blood flow (CBF) - neurovascular coupling (NVC) - is essential for normal brain function.

Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow.

The brain has impressive energy requirements and paradoxically, very limited energy reserves, implying its huge dependency on continuous blood supply. Aditionally, cerebral blood flow must be dynamically regulated to the areas of increased neuronal activity and thus, of increased metabolic demands. The coupling between neuronal activity and cerebral blood flow (CBF) is supported by a mechanism called neurovascular coupling (NVC).

Microelectrode Sensor for Real-Time Measurements of Nitrite in the Living Brain, in the Presence of Ascorbate.

The impaired blood flow to the brain causes a decrease in the supply of oxygen that can result in cerebral ischemia; if the blood flow is not restored quickly, neuronal injury or death will occur. Under hypoxic conditions, the production of nitric oxide (NO), via the classical L-arginine-NO synthase pathway, is reduced, which can compromise NO-dependent vasodilation. However, the alternative nitrite (NO) reduction to NO, under neuronal hypoxia and ischemia conditions, has been viewed as an in vivo storage pool of NO, complementing its enzymatic synthesis.

A High Fat/Cholesterol Diet Recapitulates Some Alzheimer's Disease-Like Features in Mice: Focus on Hippocampal Mitochondrial Dysfunction.

Background: Ample evidence from clinical and pre-clinical studies suggests mid-life hypercholesterolemia as a risk factor for developing Alzheimer's disease (AD) at a later age. Hypercholesterolemia induced by dietary habits can lead to vascular perturbations that increase the risk of developing sporadic AD.

Objective: To investigate the effects of a high fat/cholesterol diet (HFCD) as a risk factor for AD by using a rodent model of AD and its correspondent control (healthy animals).

Platinized carbon fiber-based glucose microbiosensor designed for metabolic studies in brain slices.

In order to understand how energy metabolism adapts to changes in neuronal activity it is imperative to perform direct measurements of the flux of glucose (and other metabolites) in brain tissue. Metabolic studies using brain slice preparations are attractive due to the controllability of recording conditions, absence of anesthetic interference and refined animal experimental protocols. In this work, taking advantage of the small size and versatility of carbon fiber microelectrodes (CFMs), we aimed to develop an amperometric glucose microbiosensor suitable for glucose measurement in brain slices.

Age-Dependent Impairment of Neurovascular and Neurometabolic Coupling in the Hippocampus.

Neurovascular and neurometabolic coupling are critical and complex processes underlying brain function. Perturbations in the regulation of these processes are, likely, early dysfunctional alterations in pathological brain aging and age-related neurodegeneration. Evidences support the role of nitric oxide (•NO) as a key messenger both in neurovascular coupling, by signaling from neurons to blood vessels, and in neurometabolic coupling, by modulating O utilization by mitochondria.

Analysis of respiratory capacity in brain tissue preparations: high-resolution respirometry for intact hippocampal slices.

The evaluation of mitochondrial function provides the basis for the study of brain bioenergetics. However, analysis of brain mitochondrial respiration has been hindered by the low yield associated with mitochondria isolation procedures. Furthermore, isolating mitochondria or cells results in loss of the inherent complexity of the central nervous system.

Combined in Vivo Amperometric Oximetry and Electrophysiology in a Single Sensor: A Tool for Epilepsy Research.

Seizures are paroxysmal events in which increased neuronal activity is accompanied by an increase in localized energetic demand. The ability to simultaneously record electrical and chemical events using a single sensor poses a promising approach to identify seizure onset zones in the brain. In the present work, we used ceramic-based platinum microelectrode arrays (MEAs) to perform high-frequency amperometric recording of local pO and local field potential (LFP)-related currents during seizures in the hippocampus of chronically implanted freely moving rats.

Neurometabolic and electrophysiological changes during cortical spreading depolarization: multimodal approach based on a lactate-glucose dual microbiosensor arrays.

Spreading depolarization (SD) is a slow propagating wave of strong depolarization of neural cells, implicated in several neuropathological conditions. The breakdown of brain homeostasis promotes significant hemodynamic and metabolic alterations, which impacts on neuronal function. In this work we aimed to develop an innovative multimodal approach, encompassing metabolic, electric and hemodynamic measurements, tailored but not limited to study SD.

Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration.

The strict energetic demands of the brain require that nutrient supply and usage be fine-tuned in accordance with the specific temporal and spatial patterns of ever-changing levels of neuronal activity. This is achieved by adjusting local cerebral blood flow (CBF) as a function of activity level - neurovascular coupling - and by changing how energy substrates are metabolized and shuttled amongst astrocytes and neurons - neuroenergetic coupling. Both activity-dependent increase of CBF and O and glucose utilization by active neural cells are inextricably linked, establishing a functional metabolic axis in the brain, the neurovascular-neuroenergetic coupling axis.

Ceramic-Based Multisite Platinum Microelectrode Arrays: Morphological Characteristics and Electrochemical Performance for Extracellular Oxygen Measurements in Brain Tissue.

Ceramic-based multisite Pt microelectrode arrays (MEAs) were characterized for their basic electrochemical characteristics and used for in vivo measurements of oxygen with high resolution in the brain extracellular space. The microelectrode array sites showed a very smooth surface mainly composed of thin-film polycrystalline Pt, with some apparent nanoscale roughness that was not translated into an increased electrochemical active surface area. The electrochemical cyclic voltammetric behavior was characteristic of bulk Pt in both acidic and neutral media.

Neurovascular uncoupling in the triple transgenic model of Alzheimer's disease: Impaired cerebral blood flow response to neuronal-derived nitric oxide signaling.

Nitric oxide (NO)-dependent pathways and cerebrovascular dysfunction have been shown to contribute to the cognitive decline and neurodegeneration observed in Alzheimer's disease (AD) but whether they represent initial factors or later changes of the disease is still a matter of debate. In this work, we aimed at investigating whether and to what extent neuronal-derived NO signaling and related neurovascular coupling are impaired along aging in the hippocampus of the triple transgenic mouse model of Alzheimer's Disease (3xTg-AD). We performed a longitudinal study combining behavior studies, in vivo simultaneous measurements of NO concentration gradients and cerebral blood flow (CBF), along with detection of NO synthase (NOS) and markers of nitroxidative stress.

Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer's disease: implications for neurometabolic regulation.

Age-dependent changes in nitric oxide ((•)NO) concentration dynamics may play a significant role in both decaying synaptic and metabolic functions in Alzheimer's disease (AD). This neuromodulator acts presynaptically to increase vesicle release and glutamatergic transmission and also regulates mitochondrial function. Under conditions of altered intracellular redox environment, (•)NO may react and produce reactive species such as peroxynitrite.

Neurovascular and neurometabolic derailment in aging and Alzheimer's disease.

The functional and structural integrity of the brain requires local adjustment of blood flow and regulated delivery of metabolic substrates to meet the metabolic demands imposed by neuronal activation. This process-neurovascular coupling-and ensued alterations of glucose and oxygen metabolism-neurometabolic coupling-are accomplished by concerted communication between neural and vascular cells. Evidence suggests that neuronal-derived nitric oxide ((•)NO) is a key player in both phenomena.

Age-associated changes of nitric oxide concentration dynamics in the central nervous system of Fisher 344 rats.

The increase in life expectancy is accompanied by an increased risk of developing neurodegenerative disorders and age is the most relevant risk factor for the appearance of cognitive decline. While decreased neuronal count has been proposed to be a major contributing factor to the appearance of age-associated cognitive decline, it appears to be insufficient to fully account for the decay in mental function in aged individuals. Nitric oxide ((•)NO) is a ubiquitous signaling molecule in the mammalian central nervous system.

Neurovascular coupling in hippocampus is mediated via diffusion by neuronal-derived nitric oxide.

The coupling between neuronal activity and cerebral blood flow (CBF) is essential for normal brain function. The mechanisms behind this neurovascular coupling process remain elusive, mainly because of difficulties in probing dynamically the functional and coordinated interaction between neurons and the vasculature in vivo. Direct and simultaneous measurements of nitric oxide (NO) dynamics and CBF changes in hippocampus in vivo support the notion that during glutamatergic activation nNOS-derived NO induces a time-, space-, and amplitude-coupled increase in the local CBF, later followed by a transient increase in local O2 tension.

Self-mixing microprobe for monitoring microvascular perfusion in rat brain.

Measuring functional activity in brain in connection with neural stimulation faces technological challenges. Our goal is to evaluate, in relative terms, the real-time variations of local cerebral blood flow in rat brain, with a convenient spatial resolution. The use of laser Doppler flowmetry (LDF) probes is a promising approach but commercially available LDF probes are still too large (450 μm) to allow insertion in brain tissue without causing damage in an extension that may negatively impact local measurements.

Nitric oxide signaling in the brain: translation of dynamics into respiration control and neurovascular coupling.

The understanding of the unorthodox actions of neuronal-derived nitric oxide ((•)NO) in the brain has been constrained by uncertainties regarding its quantitative profile of change in time and space. As a diffusible intercellular messenger, conveying information associated with its concentration dynamics, both the synthesis via glutamate stimulus and inactivation pathways determine the profile of (•)NO concentration change. In vivo studies, encompassing the real-time measurement of (•)NO concentration dynamics have allowed us to gain quantitative insights into the mechanisms inherent to (•)NO-mediated signaling pathways.

Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration.

During the last decades nitric oxide ((•)NO) has emerged as a critical physiological signaling molecule in mammalian tissues, notably in the brain. (•)NO may modify the activity of regulatory proteins via direct reaction with the heme moiety, or indirectly, via S-nitrosylation of thiol groups or nitration of tyrosine residues. However, a conceptual understanding of how (•)NO bioactivity is carried out in biological systems is hampered by the lack of knowledge on its dynamics in vivo.

Evidence for a pathway that facilitates nitric oxide diffusion in the brain.

Nitric oxide (()NO) is a diffusible messenger that conveys information based on its concentration dynamics, which is dictated by the interplay between its synthesis, inactivation and diffusion. Here, we characterized ()NO diffusion in the rat brain in vivo. By direct sub-second measurement of ()NO, we determined the diffusion coefficient of ()NO in the rat brain cortex.

Brain nitric oxide inactivation is governed by the vasculature.

The mechanisms underlying nitric oxide ((•)NO) synthesis and inactivation in the brain are essential determinants of (•)NO neuroactivity. Although (•)NO production is well characterized, the pathways of inactivation in vivo remain largely unknown. Here, we characterize the kinetics and the major mechanism of (•)NO inactivation in the rat brain cortex and hippocampus in vivo by measuring locally applied (•)NO with carbon-fiber microelectrodes (CFMs) and ceramic-based microelectrode arrays (MEAs).

In vivo modulation of nitric oxide concentration dynamics upon glutamatergic neuronal activation in the hippocampus.

Nitric oxide ((•)NO) is a labile endogenous free radical produced upon glutamatergic neuronal activity in hippocampus by neuronal nitric oxide synthase (nNOS), where it acts as a modulator of both synaptic plasticity and cell death associated with neurodegeneration. The low CNS levels and fast time dynamics of this molecule require the use of rapid analytical methods that can more accurately describe its signaling in vivo. This is critical for understanding how the kinetics of (•)NO-dependent signaling pathways is translated into physiological or pathological functions.

Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide.

Aims: Cyclosporine A (CsA) has represented a fundamental therapeutic weapon in immunosuppression for the past three decades. However, its clinical use is not devoid of side effects, among which hypertension and vascular injury represent a major drawback. Endothelial cells are able to generate reactive oxygen and nitrogen species upon exposure to CsA, including formation of peroxynitrite.