Annual Report of Activities CNC 2008 - Center for Neuroscience and ...

Free Radicals and Antioxidants in Biomedical Res. | Head: João LaranjinhaObjectivesReactive oxygen and nitrogen species play apivotal in the regulation of critical cellularfunctions but extensive oxidative damage tobiomolecules (oxidative stress) can lead to celldeath by a variety of different mechanisms, eitherby turning off vital processes or by upregulatingtoxic cascades.Long term objectives of this group are:1) To study molecular mechanisms inherent toneuromodulation, and aging that critically involvefree radicals and oxidants, particularly nitric oxide(•NO). Emphasis is put on the dynamic profiles ofNO in hippocampus in connection with itsneuromodulatory role and as the mediator ofneurovascular coupling.2) To establish molecular mechanisms underlyingthe health‐promoting role of plant‐derived dietaryphenolic compounds, particularly those present inwine, in connection with the protection againstvascular endothelial dysfunction, antiinflammatoryproperties as well as the nonenzymaticproduction of nitric oxide from dietarynitrite in the gastric compartment. Nitrite‐drivenregulatory process with impact in physiology andin pathology.Main Achievements1. We have discovered new molecules (ethylnitrite) formed in vivo in the human stomach fromthe interaction of wine ethanol and dietary nitritethat act as nitric oxide‐donors, inducing musclerelaxation and have proposed a new pathway forthe biological impact of dietary nitrite and dietarypolyphenols, beyond their well‐known antioxidantactivity.2. We have established that wine polyphenols mayexert cardioprotective effects by interfering withcell signaling pathways. In particular, resveratrolprotects vascular smooth muscle cells proliferation,promoted by oxidized LDL, by disrupting themTOR signaling pathway, pointing to a newpotential pharmacologic target in atherogenesis.Also, malvidin‐3 glucoside, a typical wineanthocyanin, was shown to protect peroxynitritetriggeredendothelial cells toxicity by up‐regulatingcellular NO and down‐regulating NF‐kB.3. We have published for the first time since nitricoxide hás been discovered, its the concentrationdynamics of nitric oxide in vivo in the rathippocampus upon stimulation of glutamateNMDA receptor.4. We have propsosed a new mechanism forneuronal protection involving glutamatedependentastrocyte gluthathionerelease.5. We have proposed a new pathwayfor cell death associated withparkinson’s disease envolving nitricoxide and dopamine metabolism6. We have developed selectiveelectrochemical micro sensors for invivo insertion into the rat brain tomeasure nitric oxide in a real‐timefashion.50