The effect of lithium on neurosteroids in SH-SY5Y cells

Fenangi C. N., Gozgoz H., Erkoc T. S., ARAYICI M. E., Doruk Ö.

TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI, 2026 (SCI-Expanded, Scopus, TRDizin)

Abstract

Objectives Although lithium (Li) remains a first-line treatment for bipolar disorder (BD), its exact mechanisms of action are still heavily debated. Because neurosteroid (NS) dysregulation plays a critical role in psychiatric disorders, this study looked into whether some of lithium's effects are mediated through altering intracellular NS levels. Methods We assessed the effects of Li (0.5-25 mM) on SH-SY5Y cell viability over 24-72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Following this, we measured intracellular NS levels at specific doses and durations via LC-MS/MS. Results While 0.5-2.5 mM Li treatments preserved cell viability, doses >= 5 mM markedly reduced it (p<0.05). At a 1 mM non-toxic dose (24 h), we noted a significant buildup in pregnenolone, progesterone, 17-OH progesterone, and dehydroepiandrosterone (DHEA) (p<0.05). Conversely, treating cells with 25 mM Li spiked pregnenolone but significantly depleted androstenedione (p<0.05), and it drove up dehydroepiandrosterone sulfate (DHEAS) across all time points. Conclusions In conclusion, Li distinctly alters neurosteroidogenesis in a dose and time-dependent manner. Although preliminary, these in vitro findings offer remarkable insights, suggesting that NS pathways might mediate lithium's clinical efficacy, warranting further comprehensive studies.