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

Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
Annals of Neurology (Impact Factor: 11.91). 05/2012; 71(5):687-98. DOI: 10.1002/ana.23536
Source: PubMed

ABSTRACT 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.
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.
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 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.
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.

Download full-text


Available from: Yiying Zhang, Jun 29, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of anesthetics and sedatives has been suggested to be a contributor to Alzheimer's disease neuropathogenesis. We wanted to address the in vivo relevance of those substances in the Tg2576 Alzheimer's mouse model. Tg7526 mice were anesthesia-sedated for 90 min once a week for 4 weeks. Y maze, Congo Red, and amyloid beta (Aβ) immunochemistry were performed. We did not find any significant change in the navigation behavior of the exposed mice compared to the controls. Significantly less deposition of Aβ in the CA1 area of the hippocampus and frontal cortex of mice exposed to isoflurane, propofol, diazepam, ketamine, and pentobarbital was observed. In the dentate gyrus, Aβ deposition was significantly greater in the group treated with pentobarbital. Congo Red staining evidenced significantly fewer fibrils in the cortex of mice exposed to diazepam, ketamine, or pentobarbital. The adopted repetitive exposure did not cause a significant detriment in Tg7526 mouse.
    Neurotoxicity Research 06/2014; 26(4). DOI:10.1007/s12640-014-9478-8 · 3.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the underlying mechanisms of isoflurane-induced cognitive impairments remain largely to be determined, neuronal inflammation and apoptosis are thought to be major contributors. Resveratrol is a naturally available herbal compound for the treatment of inflammatory and neurodegenerative diseases. We therefore aimed to investigate the effects of resveratrol on the isoflurane-induced cognitive impairments and the associated hippocampal inflammation responses and neuronal apoptosis in the aged mice. Fifteen-month-old male C57BL/6 mice received 2 h of 1.5 % isoflurane or oxygen exposure 24 h after the intraperitoneal injection of resveratrol or saline daily for 7 consecutive days. Here, we showed that the isoflurane anesthesia decreased the freezing time to context significantly at 48 h after the isoflurane exposure in the fear conditioning test. The hippocampal levels of IL-1β, TNF-α, NLRP3, cleaved caspase-3, and Bax increased significantly while the hippocampal levels of IkBα and Bcl-2 decreased significantly at 6 and/or 48 h after the isoflurane anesthesia. All these effects induced by isoflurane were attenuated by resveratrol pretreatment. However, the isoflurane anesthesia had no significant effect on the hippocampal Sirt1. In conclusion, our results suggest that resveratrol attenuates the hippocampus-dependent cognitive impairment induced by isoflurane anesthesia through its anti-inflammation and anti-apoptosis effects in aged mice.
    Journal of Molecular Neuroscience 10/2013; 52(2). DOI:10.1007/s12031-013-0141-2 · 2.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Anesthetic isoflurane has been shown to promote Alzheimer's disease (AD) neuropathogenesis by inducing caspase activation and accumulation of β-amyloid (Aβ). Phosphorylation of tau protein is another important feature of AD neuropathogenesis. However, the effects of isoflurane on phosphorylated tau levels remain largely to be determined. We therefore set out to determine whether isoflurane can increase phosphorylated tau levels. 5 to 8 month-old wild-type and AD transgenic mice [B6.Cg-Tg (APPswe, PSEN1dE9)85Dbo/J] were treated with 1.4% isoflurane for two hours. The mice brain tissues were harvested at six, 12 and 24 hours after the anesthesia. For the in vitro studies, primary neurons from wild-type and the AD transgenic mice were exposed to 2% isoflurane for six hours, and were harvested at the end of anesthesia. The harvested brain tissues and neurons were subjected to Western blot analysis by which the levels of phosphorylated tau protein at Serine 262 (Tau-PS262) were determined. Here we show that the isoflurane anesthesia increased Tau-PS262 levels in brain tissues and primary neurons from the wild-type and AD transgenic mice. Moreover, the isoflurane anesthesia may induce a greater increase in Tau-PS262 levels in primary neurons and brain tissues from the AD transgenic mice. Finally, caspase activation inhibitor Z-VAD and Aβ generation inhibitor L-685,458 attenuated the isoflurane-induced increases in Tau-PS262 levels. In conclusion, clinically relevant isoflurane anesthesia increases phosphorylated tau levels, which may result from the isoflurane-induced caspase activation and Aβ generation. These findings will promote more studies to determine the effects of anesthetics on tau phosphorylation.
    PLoS ONE 06/2012; 7(6):e39386. DOI:10.1371/journal.pone.0039386 · 3.53 Impact Factor