Article

The Common Inhalation Anesthetic Isoflurane Induces Caspase Activation and Increases Amyloid beta-Protein Level In Vivo

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Annals of Neurology (Impact Factor: 11.91). 12/2008; 64(6):618-27. DOI: 10.1002/ana.21548
Source: PubMed

ABSTRACT An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed.
We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction.
Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.
Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.

0 Bookmarks
 · 
150 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: Postoperative cognitive dysfunction (POCD) often occurs in elderly patients and may involve neuroinflammation. This study was to determine whether anesthetic choice (intravenous vs. volatile anesthetics) affects cognitive impairment and neuroinflammation in elderly rat. Total 54 twenty-month old male Fischer 344 rats were assigned randomly to control, right carotid exposure under propofol-buprenorphine or isoflurane-buprenorphine anesthesia groups. They were tested by Barnes maze and fear conditioning from 6 days after the surgery. Their brains were harvested 24 h after the surgery for quantifying interleukin (IL) 1β, tumor necrosis factor (TNF)α and ionized calcium binding adaptor molecule 1 (Iba-1). We showed that the heart rates and mean arterial blood pressure were similar during surgery under propofol-buprenorphine or isoflurane-buprenorphine anesthesia. There was no difference in the surgery-induced increase of the plasma IL-1β and TNFα levels under these two types of anesthesia. Rats subjected to surgery took longer than control rats to identify the target hole 8 days after the completion of training sessions in Barnes maze [32 ± 23 s for control, 118 ± 64 s for propofol group (P < 0.05 vs. control), 107 ± 64 s for isoflurane group (P < 0.05 vs. control)] and had less freezing behavior in the fear conditioning test. Surgery and anesthesia increased IL-1β and Iba-1 but did not affect tau phosphorylated at S199/202 and S396 in the cerebral cortex and hippocampus. Our results suggest that surgery under general anesthesia induces neuroinflammation and cognitive impairment. Anesthetic choice may not be a significant modifiable factor for these effects.
    Journal of Neuroimmune Pharmacology 02/2015; 10(1). DOI:10.1007/s11481-014-9580-y · 3.17 Impact Factor

Full-text (2 Sources)

Download
10 Downloads
Available from
Sep 16, 2014