The Potential Dual Effects of Anesthetic Isoflurane on Hypoxia-Induced Caspase-3 Activation and Increases in β-Site Amyloid Precursor Protein-Cleaving Enzyme Levels

Pan, C.; Xu, Zhipeng; Dong, Yuanlin; Zhang, Yiying; Zhang, Jun; McAuliffe, Sayre; Yue, Yun; Li, Tianzuo; Xie, Zhongcong

doi:10.1213/ane.0b013e3182185fee

Cited by 24 publications

(24 citation statements)

References 51 publications

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“…It is important and urgent to have well-designed clinical studies for confirmation of possible neurotoxic effects of general anesthetics in human developing brains. On the other hands, the patients almost always receive surgeries when they received general anesthesia, while these surgical stimulation may have significant effects on neuronal apoptosis in the developing brain induced by general anesthetics 65;66 …”

Section: Role Of Ca2+ In Anesthetics-induced Neurotoxicitymentioning

confidence: 99%

Dual effects of neuroprotection and neurotoxicity by general anesthetics: Role of intracellular calcium homeostasis

Wei

Inan

2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Although general anesthetics have long been considered neuroprotective, there are growing concerns about neurotoxicity. Preclinical studies clearly demonstrated that commonly used general anesthetics are both neuroprotective and neurotoxic, with unclear mechanisms. Recent studies suggest that differential activation of inositol 1,4,5-trisphosphate receptors, a calcium release channel located on the membrane of endoplasmic reticulum (ER), play important role on determining the fate of neuroprotection or neurotoxicity by general anesthetics. General anesthetics at low concentrations for short duration are sublethal stress factors which induce endogenous neuroprotective mechanisms and provide neuroprotection via adequate activation of InsP3R and moderate calcium release from ER. On the other hand, general anesthetics at high concentrations for prolonged duration are lethal stress factors which induce neuronal damage by over activation of InsP3R and excessive and abnormal Ca2+ release from ER. This review emphasizes the duel effects of both neuroprotection and neurotoxicity via differential regulation of intracellular Ca2+ homeostasis by commonly used general anesthetics and recommends strategy to maximize neuroprotective but minimize neurotoxic effects of general anesthetics.

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Section: Role Of Ca2+ In Anesthetics-induced Neurotoxicitymentioning

confidence: 99%

Dual effects of neuroprotection and neurotoxicity by general anesthetics: Role of intracellular calcium homeostasis

Wei

Inan

2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Recently, investigations showed dual effects (protection versus promotion) of isoflurane on Aβ-induced apoptosis, which may act through Bcl-2 family proteins [22,23]. Liu et al [24] reported that isoflurane induced spatial memory impairment through a mechanism independent of Aβ levels and tau protein, but the rats in their investigation just received 1.4% isoflurane for 2 hr.…”

Section: Discussionmentioning

confidence: 99%

“…Other investigations showed that anesthetic-induced neural damage has similar mechanisms with Alzheimer's disease (AD) [5,6]. AD presents memory loss followed by a progressive dementia and is characterized by extensive atrophy of the brain caused by series neurodegeneration, including generation of β-amyloid (Aβ), appearance of neurofibrillary tangles, and neuronal and synaptic loss [7,8].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Premedication Attenuates Isoflurane Anesthesia-Induced β-Amyloid Generation and Cholinergic Dysfunction in the Hippocampus of Aged Rats

Tan

Luo

et al. 2012

International Journal of Neuroscience

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Melatonin plays an important role in aging and relevant neurodegeneration as an antioxidant and neuroprotector. It can interact with β-amyloid (Aβ) generation, inhibit formation of β-sheet and amyloid fibrils, modulate apoptosis, and protect cholinergic system function in Alzheimer's disease animal model. Recently, its effects on anesthetic-induced neurodegeneration have received more attention, and in this investigation, we explored whether melatonin can attenuate Aβ(1-40) generation and cholinergic dysfunction in the hippocampus of aged rats induced by isoflurane through enzyme-linked immunosorbent assay, Western blot, immunohistochemistry, and immunofluorescence. The results showed that isoflurane increased Aβ(1-40) generation and caused cholinergic dysfunction through decreasing choline acetyltransferase (ChAT) expression in the hippocampus in a dose-dependent way, and intraperitoneal melatonin premedication attenuated the neurodegeneration through inhibiting Aβ(1-40) generation and increasing ChAT expression, and its effects were more obvious in high-concentration isoflurane group. Collectively, our results provide evidence for the therapeutic value of melatonin on isoflurane-induced neurodegeneration, including Aβ(1-40) generation and cholinergic dysfunction, and further work is necessary to clarify its target sites and detailed mechanisms.

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“…Isoflurane has been shown to cause dose-and duration-dependent dual effects on caspase 3 activation (protection or potentiation). 38,39 Thus, it is possible that isoflurane may induce similar dual effects on mitochondrial function (eg, mPTP opening), learning, and memory. Future studies may include a systematic investigation of the effects of isoflurane and other anesthetics (eg, desflurane, sevoflurane, and propofol) on opening of mPTP, levels of MMP, ATP, and ROS, and learning and memory function to further test this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory

Zhang

Xie

2012

Annals of Neurology

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Objective-There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined.Methods-We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test.Results-Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript levels of mitochondrial membrane potential and adenosine-5′-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.Interpretation-These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation. 3 Therefore, there is a need to identify anesthetic(s) that will not induce or that will induce to a lesser degree AD neuropathogenesis and cognitive dysfunction. This opinion has been emphasized in the fields of both AD and anesthesia research. 4 The commonly used inhalation anesthetic isoflurane has been shown to induce caspase activation and apoptosis, and to increase β-amyloid protein (Aβ) oligomerization and accumulation in vitro and in vivo. [5][6][7][8][9][10][11][12][13] Desflurane, another commonly used inhalation anesthetic, may not induce these detrimental effects in cultured cells. 13,15,16 Consequently, it is important to further assess in vivo relevance, underlying mechanisms, and functional consequences (eg, learning and memory) of these observations. Therefore, we set out to determine whether isoflurane and desflurane may have different effects on learning and memory function and on mitochondrial function (eg, mitochondrial permeability transition pore [mPTP] opening).Isoflurane, but not desflurane, could induce the caspase activation and apoptosis through the mitochondria-dependent apoptosis pathway. 16 Mitochondrial dysfunction can lead to caspase activation and apoptosis, potentially through opening of mPTP, reductions in mitochond...

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The Potential Dual Effects of Anesthetic Isoflurane on Hypoxia-Induced Caspase-3 Activation and Increases in β-Site Amyloid Precursor Protein-Cleaving Enzyme Levels

Cited by 24 publications

References 51 publications

Dual effects of neuroprotection and neurotoxicity by general anesthetics: Role of intracellular calcium homeostasis

Dual effects of neuroprotection and neurotoxicity by general anesthetics: Role of intracellular calcium homeostasis

Melatonin Premedication Attenuates Isoflurane Anesthesia-Induced β-Amyloid Generation and Cholinergic Dysfunction in the Hippocampus of Aged Rats

Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory

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