Abstract
The commonly used inhalation anesthetic isoflurane has been reported to induce DNA damage and cytotoxicity. However, the methods to attenuate these effects remain largely to be determined. Mild hypothermia has neuroprotective effects. We therefore set out to assess whether mild hypothermia could protect the isoflurane-induced DNA damage and cytotoxicity. Moreover, we investigated the underlying mechanisms by assessing the effects of mild hypothermia on the isoflurane-induced changes in ATP levels. H4 human neuroglioma cells were treated with 2% isoflurane for 3 or 6 h with and without mild hypothermia (35°C). We assessed the cell viability by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assay. We determined DNA damage by measuring levels of phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X), the marker of DNA damage. We also measured ATP levels in the cells. Here we showed that the treatment with 2% isoflurane for 6 h induced cytotoxicity and DNA damage in the cells. Moreover, the treatment with 2% isoflurane for 3 h decreased ATP levels without inducing cytotoxicity. Mild hypothermia attenuated the isoflurane-induced cytotoxicity, DNA damage, and ATP reduction in the cells. Taken together, these data suggest that the isoflurane-induced reduction in ATP levels occurred before the isoflurane-induced cytotoxicity. Isoflurane may induce DNA damage and cause cytotoxicity through reducing ATP levels. Mild hypothermia would ameliorate isoflurane-induced DNA damage and cytotoxicity by attenuating the isoflurane-induced reduction in ATP levels. These pilot studies have established a system and will promote the future investigations of anesthesia neurotoxicity.
Highlights
Inhalation anesthetic isoflurane has been reported to induce the neurotoxicity associated with Alzheimer’s disease (AD) neuropathogenesis [Eckenhoff et al, 2004; Loop et al, 2005; Wei et al, 2005, 2007; Xie et al, 2006, 2007; Lin and Zuo, 2011, reviewed in Vutskits and Xie (2016)]
Our previous studies showed that the commonly used anesthetic isoflurane was able to induce neurotoxicity associated with AD neuropathogenesis [(Xie et al, 2006, 2007; Zhang et al, 2010, 2012), reviewed in Vutskits and Xie (2016)] and DNA damage (Ni et al, 2016)
We determined whether mild hypothermia (35◦C) was able to attenuate the isoflurane-induced cytotoxicity and DNA damage
Summary
Inhalation anesthetic isoflurane has been reported to induce the neurotoxicity associated with Alzheimer’s disease (AD) neuropathogenesis [Eckenhoff et al, 2004; Loop et al, 2005; Wei et al, 2005, 2007; Xie et al, 2006, 2007; Lin and Zuo, 2011, reviewed in Vutskits and Xie (2016)]. Our recent studies have shown that isoflurane can cause DNA damage (Ni et al, 2016). Hypothermia has been shown to decrease excitotoxicity, inflammation, free radical levels, and. Mild Hypothermia Rescues Isoflurane Cytoxicity intracellular calcium overload, which would protect the apoptosis (Andresen et al, 2015). Mild hypothermia (e.g., 35◦C) is a neuroprotective strategy and could be useful to treat brain injuries (Andresen et al, 2015). It remains unknown whether mild hypothermia can protect the isoflurane-induced DNA damage and cytotoxicity
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