Linalool attenuates oxidative stress and mitochondrial dysfunction mediated by glutamate and NMDA toxicity

Abstract Mitochondrial dysfunction and inflammation contribute to the initiation and development of several brain pathological conditions, including Alzheimer’s disease and cerebral ischemia. Linalool is an aromatic plant-derived monoterpene alcohol with reported anti-inflammatory, and anti-oxidant properties. We investigated the role of linalool on glutamate-induced mitochondrial oxidative stress in immortalized neuronal HT-22 cells. Glutamate induced oxidative stress in neuronal cells, as detected by real-time cell impedance measurements, MTT assay, and analysis of Annexin V/PI. Administration of linalool 100 μM reduced cell death mediated by glutamate. Staining of glutamate-stimulated mitochondria by MitoTracker revealed improved morphology in the presence of linalool. Furthermore, we demonstrated a potential neuroprotective effect of linalool in conditions of oxidative stress by a reduction of mitochondrial ROS and mitochondrial calcium levels, and by preserving mitochondrial membrane potential. Experiments using both high-resolution respirometry and Seahorse Extracellular flux analyzer showed that linalool was able to promote an increase in uncoupled respiration that could contribute to its neuroprotective capacity. Linalool protection was validated using organotypic hippocampal slices as ex vivo model with NMDA as a stimulus to induce excitotoxity cell damage. These results demonstrate that linalool is protective in an in vitro model of glutamate-induced oxidative stress and in an ex-vivo model for excitotoxity, proposing linalool as a potential therapeutic agent against neurodegenerative brain diseases where oxidative stress contributes to the pathology of the disease.