Nicotinamide derivatives protect the blood-brain barrier against oxidative stress

Nicotinamides play a crucial role in energy metabolism and maintenance of the redox homeostasis counteracting oxidative stress and elevated reactive oxidative species (ROS) in human cells. The levels of nicotinamides decline with age and are associated with various pathologies, including ones linked with the blood-brain barrier disorder. Therefore, the investigation of the bioactivity of synthetic nicotinamide derivates (NAs) and evaluation of their potential to protect the blood-brain barrier (BBB) from oxidative stress is emerging as an important new strategy. In the current study, we tested different NAs as potential exogenous substitutes for such biological processes. All tested derivatives were non-toxic and attenuated elevation of ROS production in brain endothelial cells induced by tert-butyl hydroperoxide (tBHP), but one specifically was protective on the cell-cultured model of the BBB. The most promising NA was a derivative containing methoxy moiety (NA-4OCH₃), which not only increased cell impedance, but had a protective effect on brain endothelial cells barrier against tBHP-induced oxidative stress on several levels: reducing the ROS level and restoring the activity of glutathione, mitochondrial membrane potential, superoxide dismutase enzymes activity to the basal level. In addition, NA-4OCH₃ increased the integrity of both human and rat cell-based BBB model after tBHP-treatment seen by the elevated transendothelial electrical resistance, tight junction protein claudin-5 level as well as the decreased permeability of markers across the barrier. This study highlights novel approach to protect the BBB from oxidative stress-induced dysfunction, positioning NA-4OCH₃ as potential neuroprotective agent for ROS-mediated disease interventions, with implications for neurodegeneration and BBB.