Abstract
Abstract Lithium (Li) is a widely-used medication for the treatment of patients with bipolar disorder. Li causes different complications. One of the most important adverse effects of Li is neurotoxicity. Neurotoxicity is usually irreversible which may lead to very important complications. The symptoms of Li-induced neurotoxicity include tremor, delirium, seizures, coma, and death. In this study, we wanted to evaluate the exact sub-cellular mechanisms of Li-induced neurotoxicity. For this purpose, we used primary neuronal cortical culture for investigating lithium-induced neurotoxicity. We applied the postnatal rat pups for isolating the cortical neurons. After that, 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 mediated through lysosomal membrane leakage associated with ROS formation and reduction of MMP. Furthermore, the incubation of isolated neurons with Li 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. Besides, Li-induced neurotoxicity is a result of the generation of ROS and LP, which leads to mitochondrial/lysosomal toxic cross-talk.
Highlights
Biologicals, chemicals, metals as well as medications could be considered as the neurotoxic agents (Clausen et al, 2019; Garza-Lombo et al, 2019; Horta et al, 2019; Richardson et al, 2019; Staff et al, 2019)
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
Because of neuronal ROS formation, Li induced a rapid decline of MMP, an apparent marker of mitochondrial dysfunction (p < 0.001) (Figure 4)
Summary
Biologicals, chemicals, metals as well as medications could be considered as the neurotoxic agents (Clausen et al, 2019; Garza-Lombo et al, 2019; Horta et al, 2019; Richardson et al, 2019; Staff et al, 2019) These factors, depending on whether they affect the central or peripheral part of the brain, cause complications on the structure and function. Li induced lipid peroxidation (LP) in synaptosomes, which leads to the modification of synaptic endings and the lipid content of synaptoplasmatic membranes that leads to severe disturbances in the function of neurotransmitter uptake systems and depolarization-dependent calcium channels (Efendiev and Kerimov, 1994; Sawas and Gilbert, 1985; Sawas et al, 1986) This can lead to depression, sleep disorders, and other important neurotoxic signs (Taranova and Nilova, 1986). The rat primary neuronal cortical culture was used for evaluation of mechanisms behind the Li-induced neurotoxicity
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