Abstract
Carbamazepine (CBZ) is a widely employed anti-seizure medication that crosses the blood-brain barrier (BBB) to exert its anti-convulsant action. The effects of CBZ on components of the BBB have yet to be completely delineated. Hence the current study evaluated the effects of CBZ upon mitochondrial functionality of BBB-derived microvascular endothelial cells isolated from Albino rats. The influence of CBZ on cell viability and barrier functions were evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), lactate dehydrogenase, and electrophysiological assays over a drug concentration range of 0.1-1000 mu M. Bioenergetics effects were measured via ATP production, mitochondrial complexes I and III activities, lactate production, and oxygen consumption rates (OCRs), and mitochondrial membrane potential, fluidity and lipid content. CBZ was cytotoxic to microvascular endothelial cells in a concentration and duration dependent manner. CBZ significantly diminished the endothelial cell's barrier functions, and impacted upon cellular bioenergetics: reducing mitochondrial complex activities with a parallel decrease in OCRs and increased anaerobic lactate production. CBZ significantly decreased mitochondrial membrane potential and induced an increase of membrane fluidity and decrease in levels of mitochondrial saturated and unsaturated fatty acids. In summary, CBZ disrupted functional activity of BBB endothelial cells via damage and modification of mitochondria functionality at therapeutically relevant concentrations.