High-Dose Propofol Induces Cytotoxicity by Elevating Intracellular Ca2⁺ via GABAA Receptor and IP3R in HT22 Cells.
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Blumenberg Viktoria, Birocchi Filippo, Shih Angela, Escobar Giulia, Mucci Adele, Armstrong Alexander, Cirstea Diana, Harris Deshea L, Bozym David J, Puliafito Benjamin R, Newcomb Richard, Dhawale Tejaswini M, Johnson Patrick C, El-Jawahri Areej, Jeffrey Richard, Barselau Alexis L, Li Alex, Emmanuel-Alejandro Estelle, Cook Daniella, Lindell Kevin, Luk Samantha O, Chaffee Ryan, Yee Andrew J, Branagan Andrew, Raje Noopur, Graham Charlotte E, Hammond Sarah P, Bushman Frederic D, Roche Aoife M, Reddy Shantan, McFarland Alexander G, Chen Yi-Bin, Choi Bryan D, Mount Christopher W, Dougan Michael, Nardi Valentina, Sohani Aliyah R, Gallagher Kathleen M E, Maus Marcela V, Frigault Matthew J, Leick Mark B
Аннотация
MATERIAL AND METHODS: Mouse hippocampal neurons (HT22 cells) served as an in vitro model. Cell viability was assessed using the CCK-8 assay. Intracellular Ca2⁺ dynamics were evaluated using the Fluo-4 AM Ca2⁺ fluorescent probe to investigate the mechanisms underlying propofol-induced Ca2⁺ dysregulation.
RESULTS: Propofol exposure at 10 μM and 50 μM across all time points (2, 6, or 24 hours) showed no significant impact on cell viability. Similarly, 100 μM propofol lacked toxicity at 2 or 6 hours, but survival significantly declined after 24 hours exposure (P < 0.0001). Furthermore, 200 μM propofol decreased cell viability after 2 hours of treatment (P < 0.01), with further reduction following prolonged exposure (P < 0.05). A rapid increase in intracellular Ca2⁺ concentration was observed with 200 μM propofol (P < 0.0001), which was entirely abolished by the inhibition of the γ-aminobutyric acid type A (GABAA) receptor. Conversely, inhibition of the inositol trisphosphate receptor (IP3R) alone partially mitigated the propofol-induced Ca2⁺ elevation (P < 0.0001). Notably, chelation of elevated intracellular Ca2⁺ using BAPTA-AM fully prevented the propofol-induced decrease in cell viability (P < 0.01).
CONCLUSION: Propofol induces cytotoxicity in HT22 cells in a concentration- or time-dependent manner. Notably, cytotoxicity at 100 μM propofol was observed only after 24 hours of exposure, whereas 200 μM propofol produced rapid cytotoxicity. This rapid toxicity is mediated by activation of GABAA receptor and IP3R, which triggers the endoplasmic reticulum (ER) Ca2⁺ release and elevating intracellular Ca2⁺ concentration.