BS/MS (Pharmaceutical Chemistry and Technology Sciences), University of Palermo, Italy, 2003 Ph.D. (Mediterranean fruit culture), University of Palermo, Italy, 2008
Dr Fazzari’s research is focused on studying the generation, pharmacokinetics, and signaling actions of electrophilic lipid signaling mediators, to develop a pharmacological strategy for the treatment of cardiovascular diseases (CVD) and Parkinson’s disease (PD). The following research projects have generated very exciting results as well as grant support: Project 1 – To evaluate nitro-nitrate fatty acid (NO2-ONO2-FA) derivatives as novel cGMP-dependent and cGMP-independent signaling mediators. Organic nitrate esters (R-ONO2), long-recognized therapies for CVD, have not been detected biologically and their vasodilatory effects are attenuated by the development of nitrate tolerance and endothelial dysfunction, highlighting an urgent need for alternative therapies. Dr. Fazzari characterized nitro-nitrate intermediates (NO2-ONO2-FA) generated under gastric and inflammatory-mediated nitration reactions between dietary conjugated linoleic acid (CLA)-containing lipids and nitrogen dioxide (?NO2), a by-product of reactions of nitric oxide (?NO) and nitrite (NO2–)-derived species. NO2-ONO2-FA derivatives are a novel class of signaling mediators since they decay to an electrophilic NO2-FA product after releasing secondary nitrogen oxides at neutral or basic pH. Of note, NO2-FA are anti-inflammatory and tissue-protective signaling mediators, which induce reversible alkylation of nucleophilic cysteine (Cys) residues with consequent post-translational modification (PTM) of many functionally-significant regulatory proteins. Recently, NO2-FA have undergone Phase II trials for the treatment of kidney and pulmonary diseases. It is hypothesized that NO2-ONO2-FA derivatives would promote vasodilation and inhibit cardiovascular inflammatory responses via both cGMP-dependent and cGMP-independent signaling actions. Successful completion of the proposed research plan could lay the foundation for a safe pharmacological strategy targeting inflammatory-related CVD.
Project 2 – To evaluate the protective actions of small molecule nitroalkenes in Parkinson’s disease. To date there are no therapeutic strategies that limit the progression of Parkinson’s disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. Dr Fazzari in collaboration with Dr. Di Maio (PIND Institute) are evaluating the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO2-OA) in vitro and in vivo rat models of PD. Preliminary data showed that in N27-A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO2-OA affected multiple PD-related pathogenic events, activating Nrf2-regulated gene expression and inhibiting NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO2-OA in a sub-acute rotenone model of PD and motivate more chronic studies in rodents and primates.