Propofol Prevents Amyloid-β-Induced Neurotoxicity through Suppression of Cytosolic Ca^2＋ and MAPK Signaling Pathway in SH-SY5Y Cells

Abstract

Alzheimer’s disease （AD） is one of the most common causes of dementia, characterized by the accumulation of amyloid-β （Aβ） peptide deposits in the brain. Within an aging society, elderly patients with preoperative dementia, or those who are affected by postoperative cognitive impairment, are a major health problem. Although inhalation anesthetics induce accumulation of Aβ protein and progression of AD, propofol, a short-acting intravenous anesthetic, has gained increasing attention for its neuroprotective effects following cerebral ischemia. However, the protective action of propofol against Aβ-induced neuronal damage remains unclear. Therefore, the aim of this study was to elucidate the mechanisms underlying the protective effect of propofol against Aβ-induced neurotoxicity. Neural damage was induced in human neuroblastoma cells （SH-SY5Y） using 2.5µM Aβ（1–42）. Cells were pretreated with propofol （1µM） for 1h, followed by further treatment with propofol for 20h in combination with Aβ. In Aβ（1–42）-induced neural damage, caspase-3 activation was increased, as was phosphorylation of p38 mitogen-activated protein kinase （MAPK） and tau. Moreover, cell viability and the phosphorylation of Akt, cAMP response element-binding protein, and Bcl-2 decreased significantly with Aβ treatment. However, these responses were reversed by pretreatment with propofol and p38MAPK inhibitor. The Aβ（1–42）-induced increase in reactive oxygen species generation was inhibited by propofol pretreatment, but remained unchanged following pretreatment with the p38MAPK inhibitor. Furthermore, Aβ（1–42）-treated cells exhibited a significant increase in cytosolic Ca^2＋（［Ca^2＋］_i）, but propofol pretreatment resulted in a significant decrease in ［Ca^2＋］_i starting 30s after exposure to Aβ（1–42）. Our results indicate that the mechanism underlying the protective effect of propofol against Aβ-induced neurotoxicity is a decrease in ［Ca^2＋］_i, which subsequently suppresses oxidative stress, along with p38MAPK and tau phosphorylation. Thus, these findings suggest that propofol, at clinically relevant concentrations, is likely to be safe in elderly patients and in those with risk factors for AD.