Inhaled Anesthetics Have Differential Experimental Effect on Memory Mechanisms
Inhaled Anesthetics Have Differential Experimental Effect on Memory Mechanisms
Abstract & Commentary
By Halinder S. Mangat, MD, Assistant Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Mangat reports no financial relationships relevant to this field of study.
Synopsis: Isoflurane causes mitochondrial disruption and apoptosis in neuronal and hippocampal cells, and decreases memory consolidation in mice. Such effects are not seen with desflurane. This may impact selection of anesthetic agents for patients with Alzheimer's disease undergoing surgical procedures.
Source: Zhang Y, et al. Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory. Ann Neurol 2012;71:687-698.
There are a large number of patients with alzheimer's disease (AD) who need and undergo surgery and anesthesia every year. Cognitive dysfunction has been reported postoperatively, placing patients with AD at increased risk. Therefore, these investigators studied cellular mechanisms that may play a role.
The authors studied caspase 3 activation, mitochondrial destabilization via reactive oxygen species (ROS) generation, and decreased levels of ATP. Hippocampal neurons and neuroblastoma cell line B104 were used. Behavioral testing in mice treated with isoflurane or desflurane was done using fear conditioning test.
Results showed isoflurane but not desflurane increased ROS generation, lowered mitochondrial membrane potential, increased caspase 3 activation, and lowered ATP levels. Many of these were mediated via opening of the mitochondrial permeability transition pore (mPTP). These effects were attenuated by cyclosporine A, a potent mPTP blocking agent. Behavioral testing showed decreased fear conditioning by isoflurane, likely from decreased memory consolidation.
The inference from this study is that isoflurane activates pathways that have been shown to be involved in the pathogenesis of AD and mimics failure of memory consolidation. This would make desflurane an anesthetic of better choice over isoflurane in patients with AD. Therefore, it would be important to emphasize the selection of anesthetic agents in patients with AD who undergo surgery.
Commentary
Inhaled anesthetics, such as isoflurane and desflurane, affect cognitive function in humans. In a clinical trial involving 45 patients undergoing non-neurological surgery, isoflurane anesthesia was associated with higher impairment in cognitive tests compared to spinal anesthesia or desflurane.1 The latter also has a lower incidence of cognitive impairment compared to propofol.2
The mechanisms behind such cognitive impairment may be numerous. Isoflurane causes increased generation of Ab.3 It has been shown to cause loss of neural stem cells and decreased neurogenesis in young rodents. These effects were not seen in adult rodents, implying an age-dependent mechanism.4 In the opposite spectrum, it induces NMDA receptor NR2B subunit composition. This is responsible for LTP in hippocampal CA1 neurons and memory formation.5 In another study, isoflurane induced cognitive impairment in mice with the lowest administered dose, but this did not persist at 56 hours post anesthesia.6
This study examines the effects of isoflurane and desflurane on some of the pathways that are involved in pathogenesis of AD. The test of memory used in this experiment is that of associative memory. A more elaborate test of memory would be a Morris water maze or a radial T-maze.
Caspase 3 activation and mitochondrial ATP depletion are important mechanisms. There are other pathological mechanisms that are also affected by isoflurane as above. The overall balance seems to indicate a detrimental effect on cognition. That the pathways of injury seem to be similar to those seen in AD should make the use of isoflurane a matter of caution in patients with AD.
References
1. Zhang B, et al. The effects of isoflurane and desflurane on cognitive function in humans. Anesth Analg 2012;114:410-415.
2. Royse CF, et al. The influence of propofol or desflurane on postoperative cognitive dysfunction in patients undergoing coronary artery bypass surgery. Anaesthesia 2011;66:455-464.
3. Wie H, Xie Z. Anesthesia, calcium homeostasis and Alzheimer's disease. Curr Alzheimer Res 2009;6:30-35.
4. Zhu C, et al. Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult rodents. J Cereb Blood Flow Metab 2010;30:1017-1030.
5. Rammes G, et al. Isoflurane anaesthesia reversibly improves cognitive function and long-term potentiation (LTP) via an up-regulation in NMDA receptor 2B subunit expression. Neuropharmacology 2009;56:626-636.
6. Valentim AM, et al. Effects of depth of isoflurane anaesthesia on a cognition task in mice. Br J Anaesth 2008;101:434-435.
Isoflurane causes mitochondrial disruption and apoptosis in neuronal and hippocampal cells, and decreases memory consolidation in mice. Such effects are not seen with desflurane. This may impact selection of anesthetic agents for patients with Alzheimer's disease undergoing surgical procedures.Subscribe Now for Access
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