Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis

Background: In human cortical neural progenitor cells, we investigated the effects of propofol on calcium homeostasis in both the ryanodine and inositol 1,4,5-trisphosphate calcium release channels. We also studied propofol-mediated effects on autophagy, cell survival, and neuro-and gliogenesis. Methods: The dose-response relationship between propofol concentration and duration was studied in neural progenitor cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays. The effects of propofol on cytosolic calcium concentration were evaluated using Fura-2, and autophagy activity was determined by LC3II expression levels with Western blot. Proliferation and differentiation were evaluated by bromodeoxyuridine incorporation and immunostaining with neuronal and glial markers. Results: Propofol dose-and time-dependently induced cell damage and elevated LC3II expression, most robustly at 200 mu M for 24 h (67 +/- 11% of control, n = 12 to 19) and 6 h (2.4 +/- 0.5 compared with 0.6 +/- 0.1 of control, n = 7), respectively. Treatment with 200 mu M propofol also increased cytosolic calcium concentration (346 +/- 71% of control, n = 22 to 34). Propofol at 10 mu M stimulated neural progenitor cell proliferation and promoted neuronal cell fate, whereas propofol at 200 mu M impaired neuronal proliferation and promoted glial cell fate (n = 12 to 20). Cotreatment with ryanodine and inositol 1,4,5-trisphosphate receptor antagonists and inhibitors, cytosolic Ca2+ chelators, or autophagy inhibitors mostly mitigated the propofol-mediated effects on survival, proliferation, and differentiation. Conclusions: These results suggest that propofol-mediated cell survival or neurogenesis is closely associated with propofol's effects on autophagy by activation of ryanodine and inositol 1,4,5-trisphosphate receptors.