Areas of focus
The group´s research programs address:
(a) The molecular mechanisms inherent in neuromodulation and aging under an umbrella that characterizes the bidirectional communication between neurons and microvasculature by addressing quantitatively, in vivo, and in real-time the role of nitric oxide as a diffusional intercellular messenger, coordinating the neurovascular and neurometabolic coupling axis. The study of the neurovascular-neurometabolic coupling axis, encompasses mechanistic as well nutritional approaches with potential to restore the functionality of neurovascular coupling and cognition.
(b) Technological innovation in terms of the project, design and implementation of microarray technology consisting of micro(bio)sensors for the real-time monitoring of neuromodulators, neurotransmitters and metabolic intermediates in the brain of anesthetized and conscious, freely behaving animals. This program is developed in collaboration with the Center for Microelectrode Technology, University of Kentucky (Lexington, USA).
(c) The mechanisms of action of plant-derived dietary phenolic compounds in terms of protection against vascular endothelial dysfunction, anti-inflammatory properties, as well as their impact on nitrite-driven regulatory processes along the nitrate:nitrite:nitric oxide pathway, encompassing the non-enzymatic production of nitric oxide from dietary nitrite in the gastric compartment and the brain.
Nitric Oxide Concentration Dynamics in the Brain
In the nervous system, nitric oxide is produced upon activation of the NMDA-type of glutamate receptor. Nitric oxide can act as a neuromodulator, regulating neuromolecular phenomena associated with memory and aging. Additionally, nitric oxide has been implicated in pathophysiological processes underlying neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, among others).
Our group is interested in the understanding of nitric oxide concentration dynamics in the hippocampus and how different concentration profiles effect critical phenomena such as tissue oxygen concentration, usage and distribution and regulation vascular tone by neuronal activity (neurovascular coupling).
To address this questions experimentally, we perform real-time and simultaneous recording of nitric oxide, oxygen and/or blood flow both in ex vivo models (ex: hippocampal slices) and in vivo (wild type healthy animals and in disease models).
The Nitrite-to-Nitric Oxide Pathway in the Gastric Compartment
We established the proof of concept that, in the presence of nitrite, polyphenol-containing dietary products induce a strong increase of nitric oxide in the stomach of humans, which, in turn, may diffuse the gastric wall reaching mucosal blood vessels, and elicit local relaxation. This points to a diet-dependent production of the ubiquitous cell modulator, nitric oxide.
In our lab we use a range of experimental strategies, ranging from in vitro biochemistry to in vivo animal models and experiments on humans to better understand this pathway of nitric oxide production out of canonic enzymatic control, as well as gain further insight into the physiological and pathophysiological outcome in the gastric compartment.
Polyphenols, Endothelial Function and Atherosclerosis
The endothelium appears to be a central player in atherogenesis, which is a chronic inflammatory process where overproduction of oxidative species and apoptosis are implicated in disease progression. Beyond their antioxidant properties, polyphenols (e.g., malvidin-3-glucoside) inhibit peroxynitrite-triggered endothelial cell apoptosis disrupting the mitochondrial pathway through modulation of Bcl-2 intracellular levels and by up-regulating cellular nitric oxide and down-regulating NF-kB. Using cellular models (BAEC), a line of research is aimed to determine how polyphenols found in our diet can afford protection against peroxynitrite-promoted endothelial cell toxicity.
Our research incorporates both, scientific and technological components. The development of selective microelectrodes for nitric oxide to be inserted in the rat brain (in vivo and ex vivo) has been carried out in collaboration with the Center for Microlectrode Technology, University of Kentuky (CenMet, Lexington, USA), of which our lab became the Coimbra Lab Division of CenMet.