The Potential Dual Effects of Anesthetic Isoflurane on Aβ-Induced Apoptosis

Zhipeng      Xu; Yuanlin      Dong; Xu      Wu; Jun      Zhang; Sayre      McAuliffe; Chuxiong      Pan; Yiying      Zhang; Fumito      Ichinose; Yun      Yue; Zhongcong      Xie

Abstract

β-amyloid protein (Aβ)-induced neurotoxicity is the main component of Alzheimer7apos;s disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Aβ levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Aβ-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naive mice, and naive mice were treated with Aβ and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined. Here we show for the first time that the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Aβ-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Aβ-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Aβ-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Aβ-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Aβ-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.

Keywords: Anesthesia, Alzheimer's disease, isoflurane, apoptosis, β Amyloid protein, dual effects,, cytosolic calcium, dementia, APP processing, endoplasmic reticulum, isoflurane treatments