Abstract
The mitochondrial membrane potential (ΔΨm) is an important factor for apoptosis, and it is produced by the proton electrochemical gradient (ΔµH(+)). Therefore, the intracellular proton concentration (pH(in)) is an important factor for modifying the ΔΨm. However, the effects of lidocaine on pH(in) are unclear. To investigate mitochondrial responses to lidocaine, therefore, we simultaneously measured pH(in) with ΔΨm, flavin adenine dinucleotide (FAD), and reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence, and calculated the FAD/NADH ratio (redox ratio), the superoxide production in mitochondria. Morphological change and early apoptosis were observed by annexin-V FITC staining under fluorescent microscope. The ratiometric fluorescent probe JC-1 and HPTS were used for the simultaneous measurements of ΔΨm with pH(in) in rat dorsal root ganglion (DRG) neurons. FAD and NADH autofluorescence were simultaneously measured, and the FAD/NADH fluorescence ratio (redox ratio) was calculated. The superoxide was measured by mitosox-red fluorescent probe for mitochondrial superoxide. Lidocaine was evaluated at 1, 5, and 10mM. Morphological change and early apoptosis were observed after 10mM lidocaine administration. Lidocaine depolarized ΔΨm with increased pH(in) in a dose-dependent manner. In low-pH saline (pH 6), in the presence of both the weak acids (acetate and propionate), lidocaine failed to depolarize ΔΨm and increase pH(in). On the other hand, lidocaine decreased the redox ratio in the cell and increased the levels of superoxide in a dose-dependent manner. These results demonstrated that lidocaine depolarizes ΔΨm by intracellular alkalization. These results may indicate one of the mechanisms responsible for lidocaine-induced neurotoxicity.
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