Lithium attenuates bupivacaine-induced neurotoxicity in vitro through phosphatidylinositol-3-kinase/threonine-serine protein kinase B- and extracellular signal-regulated kinase-dependent mechanisms.

Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. Lithium is a mood stabilizer for the treatment of bipolar disorder and may exert neuroprotective effects. In this study, we evaluated the effects of lithium on bupivacaine (a frequently used LAs)-induced injury in mouse neuroblastoma neuro 2a (N2a) cells. N2a cells were treated with bupivacaine in the presence or absence of lithium. After treatment, the cell injury was evaluated by examination of viability, morphology changes, and nuclear condensation. The levels of mitochondrial transmembrane potential (ΔΨm) and activation of phosphatidylinositol-3-kinase (PI3K)/ threonine-serine protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also examined. In a separate experiment, we investigated the effect of Akt and ERK inhibition on cell injury after bupivacaine and lithium treatment. Pretreatment of N2a cells with lithium significantly attenuated bupivacaine-induced cell injury. Lithium pretreatment completely reversed the suppression of PI3K/Akt and ERK signalings and significantly prevented the decline of ΔΨm in N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERK diminished the protective effect of lithium against bupivacaine-induced neuronal death. Our data suggest that lithium pretreatment provides a protective effect on bupivacaine-induced neuronal cell injury. This action of lithium is mediated through, at least in part, the activating of PI3K/Akt- and ERK-dependent mechanisms. Because lithium is a clinically proved safety drug for neurons, it is worthwhile to identify whether coadministration of LAs with lithium will decrease the risks of LAs-induced postoperative neurological complications in clinic practice.