A synthetic cell permeable antioxidant protects neurons against acute oxidative stress

Abstract

Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinson’s disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and moderate mitochondrial enrichment of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against cell loss in a zebrafish model of dopaminergic neurodegeneration.

Delocalization of the Unpaired Electron in the Quercetin Radical: Comparison of Experimental ESR Data with DFT Calculations

“…The principle of the protective effect of a free radical scavenger antioxidant is that (i) the antioxidant quickly takes over the high energy contained in a reactive free radical, (ii) the energy is stabilized by forming a relatively un-reactive antioxidant radical, and (iii) the energy is safely channeled in the antioxidant network of the cell [10]. Q is one of the most studied free radical scavengers because of its extraordinary high potency and, therefore, we focused on this compound [7,15]. In the first step, Q donates an electron to the free radical through hydrogen atom transfer (HAT), sequential proton-loss electron transfer (SET-PT), or single electron transfer followed by proton loss (SPLET), depending on the solvent.…”

“…For example, by accepting an electron, the hydroxyl radical is converted into the hydroxyl anion that, after protonation, becomes water [1,5,6]. In the protection against ROS, Q takes over the energy of the ROS and channels this energy in the antioxidant network of the body [7]. When Q takes over the energy, it is firstly oxidized to a quercetin radical (Q • ).…”

Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

“…Reactive oxygen species are a causal factor in the process of aging and the cumulative damage has been associated with AD [45]. In this study, the DPPH radical scavenging activity of the newly synthesized compounds was estimated using the Brand-Williams method.…”

Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target

“…Through a combination of techniques, we have identified gene expression profiles and miRNA signatures that strongly indicate that an alteration in mitochondrial biogenesis and function are among the key determinants behind increased VEGF production and accelerated cell proliferation. To test our conclusions, we have also treated LAM cell lines with the potent, mito-targeting and mito-active drug candidate Proxison [11] and observed restoration of mitochondrial function and a corresponding reduction in VEGF production and proliferation capacity.…”