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.

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Available from: Yiying Zhang, Jul 30, 2015
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    • "Interestingly, despite experimental design differences , this protective effect could also be a factor in the repetitive exposures performed here. However, negative effects to isoflurane exposure were also described (Mandal and Fodale 2009; Zhang et al. 2012, 2013), and more studies are needed to clarify this aspect, most of all regarding the link between memory and behavioral impairment and the site of cortical histological changes. "
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    • "The pro-apoptotic molecules of Bax and anti-apoptotic members of the Bcl family are associated with the dysfunction of mitochondrial membrane on the mitochondrial apoptotic pathway (Zhang et al. 2012; Renault et al. 2013). It has been suggested that isoflurane stimulates the mitochondrial apoptotic pathway and ultimately activates the caspase-3 or caspase- 9 (Kong et al. 2013; Zhang et al. 2012). Shen et al. (2012) have demonstrated that resveratrol contributes to cell survival by inhibiting the caspase-3 activity and leading to a high expression of Bcl-2 and a low expression of Bax, which is closely related with the mitochondria pathway of apoptosis. "
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