Inositol-Dependent Alleviation of Lithium-Induced Embryonic Neurotoxicity in Mice Through the GSK3β/β-Catenin/CyclinD1 Pathway

Lithium carbonate (Li2CO3) is a first-line pharmacotherapy for bipolar disorder (BPD) in female patients of childbearing age, although it is associated with embryonic teratogenicity. Lithium exposure in batteries and pharmaceuticals has been a toxicity factor for women’s reproductive health in energy, environment, and fitness fields. Neural tube defects (NTDs) are the severest reproductive outcome of maternal Li2CO3 exposure. Currently, there is a lack of effective prevention for Li2CO3 neurotoxicity. Our previous study revealed that lithium-induced murine NTDs correlated with enhanced proliferation and impaired inositol biosynthesis. In this study, 400 mg/kg inositol was used to treat the lithium-induced murine NTDs after calculating the toxicity using ADMETlab 3.0 and Deep-PK. We found that inositol supplementation ameliorated fetal neural phenotypes, crown-rump length, and body weight and rescued aberrant cell proliferation and dysregulated the GSK3β/β-catenin/CyclinD1 pathway in both animal and cellular models. The affinity of GSK3β-inositol interaction was analyzed and validated using molecular dynamics and surface plasmon resonance. GSK3β-edited cell models further revealed that inositol altered GSK3β post-transcriptional status and phosphorylation, consequently modulating the GSK3β/β-catenin/CyclinD1 signaling cascade. Overall, our study clarified that inositol alleviates lithium-induced NTDs via the GSK3β/β-catenin/CyclinD1 pathway, revealed the direct molecular interaction between inositol and GSK3β, and highlighted the potential of inositol as a therapeutic prevention against lithium-induced embryonic neurotoxicity for childbearing female BPD patients.