Article

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.

1 Follower
 · 
341 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anesthetic isoflurane has been reported to induce caspase-3 activation. The underlying mechanism(s) and targeted intervention(s), however, remain largely to be determined. Vitamin C (VitC) inhibits oxidative stress and apoptosis. We therefore employed VitC to further determine the up-stream mechanisms and the down-stream consequences of the isoflurane-induced caspase-3 activation. H4 human neuroglioma cells overexpressed human amyloid precursor protein (H4-APP cells) and rat neuroblastoma cells were treated either with (1) 2 % isoflurane or (2) with the control condition, plus saline or 400 μM VitC for 3 or 6 h. Western blot analysis and fluorescence assay were utilized at the end of the experiments to determine caspase-3 activation, levels of reactive oxygen species and ATP, and mitochondrial function. The interaction of isoflurane (1.4 % for 2 h) and VitC (100 mg/kg) on cognitive function in mice was also assessed in the fear conditioning system. Here, we show for the first time that the VitC treatment attenuated the isoflurane-induced caspase-3 activation. Moreover, VitC mitigated the isoflurane-induced increases in the levels of reactive oxygen species, opening of mitochondrial permeability transition pore, reduction in mitochondrial membrane potential, and the reduction in ATP levels in the cells. Finally, VitC ameliorated the isoflurane-induced cognitive impairment in the mice. Pending confirmation from future studies, these results suggested that VitC attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings would promote further research into the underlying mechanisms and targeted interventions of anesthesia neurotoxicity.
    Molecular Neurobiology 11/2014; DOI:10.1007/s12035-014-8959-3 · 5.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Postoperative cognitive dysfunction (POCD) is a decline in cognitive performance after a surgery with anaesthesia. The exact reasons of surgery and/or anaesthesia resulting in POCD are unclear. The aim of this study is to investigate the effects of different concentration and duration time of isoflurane anaesthesia on cognitive performance and cellular mechanisms involved in learning and memory function. In present work, young adult male C57BL/6 mice (age: 8 weeks) were anaesthetized by different concentration isoflurane in 100% oxygen for different duration time (Mice in group I1 received 0.7% isoflurane 0.5 h, mice in I2 received 0.7% isoflurane 2 h, mice in I3 received 1.4% isoflurane 2 h, and mice in I4 received 1.4% isoflurane 4 h). Non-anaesthetized mice served as control group (I0). Spatial learning was assessed at 10 days post-anesthesia in Morris water maze (MWM). Hippocampal protein expressions of activated caspase 3, NMDA receptor subunit NR2B, and extracellular-signal regulated kinase (ERK) 1/2 were evaluated 24 hours and 2 weeks post anesthesia. Protein expression of activated caspase3 was detected acute elevated in I3 (24 h post-anesthesia) and acute and long-term elevated in I4 (24 hours and 2 weeks post-anesthesia). There was no significant difference between I1, I2 and control group. Protein expressions of NR2B showed an acute and long-term increasement in I1 and I2, decreasement in I4, and an acute decline, then returned to normal in I3 compared to control group. The ratio of phosopho-ERK1/2 to total-ERK showed an acute increasement in I1 and I2, then came to normal 2 weeks post anesthesia compared to control group, meanwhile, we detected an acute and long-term decline in I3 and I4. In MWM test, mice in I1 and I2 showed cognitive improvement, mice in I3 showed similar to control group, while mice in I4 demonstrated cognitive impairment, which were approximately corresponding to the changes of protein expression of NR2B and activation of ERK1/2. The present data suggested the following: (1) Isoflurane may cause neurotoxicity by inducing caspase activation and apoptosis with the anesthetic concentration increased and duration prolonged. (2) Low concentration of isoflurane in 2 hours can induce a hippocampus-specific elevation of NR2B subunit composition and ratio of p-ERK1/2 to total ERK1/2, produce hippocampal-dependent cognitive improvement. While high concentration of isoflurane exceeding 4 hours may induce a decline of NR2B and ratio of pERK1/2 to ERK1/2, then result in cognitive impairment.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The effect of anesthesia on the developing brain has attracted more attention and arguments. This review summarizes various studies on developmental neurotoxicity induced by anesthesia, particularly focuses on the function of the mitochondrial dysfunction. Experimental results present evidence that general anesthesia can cause mitochondrial dysfunction via complex pathways, including oxidative stress, electron transport chain dysfunction, mitochondrial dynamics, calcium homeostasis, and mitochondrion-dependent apoptotic pathway. Hence, the molecular processes of mitochondrial dysfunction should be understood to develop novel therapeutic strategies that can prevent anesthesia-induced neurotoxicity and provide neuroprotection against developmental central nervous system.
    Brain Research Bulletin 10/2014; 110. DOI:10.1016/j.brainresbull.2014.10.011 · 2.97 Impact Factor

Full-text

Download
217 Downloads
Available from
Jun 1, 2014