Effects of lithium, valproic acid and lamotrigine on apoptosis, oxidative stress and TRPM2 channel activity in experimental bipolar nerve cell culture model

The pathophysiology of bipolar disorder (BD) is widely recognized to entail oxidative damage, apoptosis, and dysregulated calcium signaling. Recent studies indicated the antioxidant, anti-apoptotic, and calcium signaling-modulating properties of lithium (Li), valproic acid (VPA), and lamotrigine (LMT), which are frequently employed in the management of mood stabilization in patients with BD. The TRPM2 cation channel is activated by oxidative stress, although it is inhibited by carvacrol (CARV) and N-(p-amycinnamoyl) anthranilic acid (ACA). This study aimed to examine the protective action of Li, VPA, and LMT against oxidative stress and apoptosis in the experimental BD-induced human SH-SY5Y neuronal cells. SH-SY5Y cells were categorized into eight distinct groups: control, Li, VPA, LMT, ouabain (OUA), OUA+Li, OUA+VPA, and OUA+LMT. At the end of the experiments, plate reader, laser confocal microscope, and cell counter analyses were performed in the cells. Compared to the control cell group, Li, VPA and LMT-treated groups had no negative effects on parameters such as apoptosis levels, cell viability, cell death rates, debris amount, caspase-3, caspase-8 and caspase-9 levels, mitochondrial dysfunction (MiHP), cytosolic reactive oxygen species (ROS) levels and calcium signaling dynamics. Incorporating Li, VPA, and LMT into OUA-treated cells led to a reduction in cellular debris and an augmentation of cell count. The incubation of OUA-treated cells with Li, VPA, LMT, and TRPM2 antagonists (ACA and CARV) led to enhanced cell viability, alongside a decrease in apoptosis, cell death, caspase activity, MiHP, and ROS levels. In conclusion, present results support that Li, VPA, and LMT treatments have no neurotoxic effects on neuronal cells and may protect against BD-induced neurotoxicity. These findings suggest that Li, VPA and LMT treatments regulate calcium signaling by blocking the TRPM2 channel, reduce oxidative stress and apoptosis, and may prevent bipolar disorder-induced neuronal damage.