Mood Stabilizers (Lamotrigine, Lithium, and Valproic Acid) Decrease Bipolar Disease Model (Ouabain)‐Induced Oxidative Stress and Apoptosis Through the Inhibition of the TRPM2 Channel in Neuronal Cells

Background Bipolar disease (BD) has been strongly associated with the etiologies of mitochondrial reactive oxygen species (mROS), apoptosis, and Ca 2+ influx. With the exception of BD, a number of neurological disorders have been linked to apoptosis and neuronal death mediated by mROS‐dependent activated TRPM2 channel stimulation. Lamotrigine (LMT), lithium (Li), and valproic acid (VPA) are mood stabilizers in BD, and they have strong antioxidant roles. However, the molecular mechanisms underlying LMT, Li, and VPA neuroprotection through TRPM2 channel inhibiton remain elusive in BD. Aim We evaluated the protective actions of LMT, Li, and VPA on BD (ouabain, OUA)‐induced oxidative neurotoxicity in SH‐SY5Y neuronal cells by modulating TRPM2. Methods The SH‐SY5Y cells were divided into nine groups as follows: control, Li, VPA, LMT, OUA, OUA + Li, OUA + VPA, LMT + VPA, and OUA + TRPM2 antagonists (N‐(p‐amylcinnamoyl)anthranilic acid or carvacrol). Results OUA exposure and TRPM2 agonist (H 2 O 2 and ADP‐ribose)‐induced TRPM2 stimulation and TRPM2 current densities were downregulated by the treatments of TRPM2 antagonist, Li, VPA, and LMT. The OUA‐induced upregulations of mROS, cytosolic ROS, lipid peroxidation, mitochondrial membrane dysfunction, apoptosis, Zn 2+ , cell death, and caspase‐3, ‐8, and ‐9 values were also downregulated through the increases of cell viability, glutathione, and glutathione peroxidase by the treatments. Conclusions The treatments of Li, VPA, and LMT modulate OUA‐mediated mROS, apoptosis, Zn 2+ , glutathione, and TRPM2‐mediated excess Ca 2+ influx. This could potentially offer protection against BD linked to elevated levels of mROS, Ca 2+ , and Zn 2+ .