beta-amyloid protein (A beta)-induced neurotoxicity is the main component of Alzheimer'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 A beta levels. We therefore set out to determine whether isoflurane can induce dose-and time-dependent dual effects on A beta-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from nave mice, and nave mice were treated with A beta 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 A beta-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 A beta-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the A beta-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the A beta-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 A beta-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.
基金:
National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K08NS048140, R21AG029856, R01 GM088801, R01GM079360]; American Geriatrics Society; Alzheimer's AssociationAlzheimer's Association; China National Science FoundationNational Natural Science Foundation of China (NSFC) [NSF30928026]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL101930] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM079360, R01GM088801] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [K08NS048140] Funding Source: NIH RePORTER; NATIONAL INSTITUTE ON AGINGUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [R21AG029856] Funding Source: NIH RePORTER
第一作者机构:[1]Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Anesthesia Crit Care & Pain Med,Dept Neurol, Geriatr Anesthesia Res Unit,Genet & Aging Res Uni, Charlestown, MA 02129 USA[2]Harvard Univ, Sch Med, Charlestown, MA 02129 USA
共同第一作者:
通讯作者:
通讯机构:[1]Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Anesthesia Crit Care & Pain Med,Dept Neurol, Geriatr Anesthesia Res Unit,Genet & Aging Res Uni, Charlestown, MA 02129 USA[2]Harvard Univ, Sch Med, Charlestown, MA 02129 USA[*1]Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Anesthesia Crit Care & Pain Med,Dept Neurol, Geriatr Anesthesia Res Unit,Genet & Aging Res Uni, 149 13th St,4310, Charlestown, MA 02129 USA
推荐引用方式(GB/T 7714):
Xu Zhipeng,Dong Yuanlin,Wu Xu,et al.The Potential Dual Effects of Anesthetic Isoflurane on A beta-Induced Apoptosis[J].CURRENT ALZHEIMER RESEARCH.2011,8(7):741-752.doi:10.2174/156720511797633223.
APA:
Xu, Zhipeng,Dong, Yuanlin,Wu, Xu,Zhang, Jun,McAuliffe, Sayre...&Xie, Zhongcong.(2011).The Potential Dual Effects of Anesthetic Isoflurane on A beta-Induced Apoptosis.CURRENT ALZHEIMER RESEARCH,8,(7)
MLA:
Xu, Zhipeng,et al."The Potential Dual Effects of Anesthetic Isoflurane on A beta-Induced Apoptosis".CURRENT ALZHEIMER RESEARCH 8..7(2011):741-752