A new approach on lithium-induced neurotoxicity using rat neuronal cortical culture: Involvement of oxidative stress and lysosomal/mitochondrial toxic Cross-Talk

Lithium (Li) is a widely-used medication for the treatment of patients with bipolar disorder. This well-known medication causes different complications. One of the most important adverse effect of Li is neurotoxicity. Neurotoxicity is usually irreversible and may lead to more serious health problems. The symptoms of Li-induced neurotoxicity include tremor, delirium, drowsiness, ataxia, muscle weakness and twitching, slurred speech, psychomotor slowing, disorientation, seizures, coma and death. In this study, we wanted to evaluate the exact sub-cellular and molecular mechanisms of Li-induced neurotoxicity.For this purpose, we used primary neuronal cortical culture for investigating lithium-induced neurotoxicity. The primary neuronal culture has a lot of benefits. The greatest advantage of primary nerve cell culture is that it makes living neurons immediately accessible to observation and manipulation. So, the postnatal rat pups were used for isolating the cortical neurons. We evaluated neural viability, neural reactive oxygen specious (ROS), lipid peroxidation, mitochondrial membrane potential (MMP), lysosomal membrane integrity (LMI), and reduced (GSH) and oxidized (GSSG) glutathione.Our results demonstrated that the cytotoxic effect of Li has interceded through lysosomal membrane leakage associated with ROS generation and reduction of MMP before cell lysis started. Incubation of isolated neurons with Li also caused rapid GSH depletion (as GSSG efflux) as another marker of cellular oxidative stress.We concluded that Li causes neurotoxicity in a dose-dependent manner. Furthermore, Li-induced neurotoxicity is a result of the generation of ROS and lipid peroxidation that leads to mitochondrial/lysosomal toxic cross-talk.

Keywords:

lithium , neurotoxicity , neuronal cortical culture , mitochondria , lysosome