Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory

Self Cite

DNA damage is associated with aging and neurological disorders, including Alzheimer’s disease. Isoflurane is a commonly used anesthetic. It remains largely unknown whether isoflurane induces DNA damage. Phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X) is a marker of DNA damage. We therefore set out to assess the effects of isoflurane on γH2A.X level in H4 human neuroglioma cells and in brain tissues of mice. Oxidative stress, caspase-activated DNase (CAD), and the p53 signaling pathway are involved in DNA damage. Thus, we determined the interaction of isoflurane with reactive oxygen species (ROS), CAD, and p53 to illustrate the underlying mechanisms. The cells were treated with 2 % isoflurane for 3 or 6 h. The mice were anesthetized with 1.4 % isoflurane for 2 h. Western blot, immunostaining and live cell fluorescence staining were used in the experiments. We showed that isoflurane increased levels of γH2A.X, cleaved caspase-3, and nucleus translocation of CAD and decreased levels of inhibitor of CAD (ICAD) and p53. Isoflurane enhanced the nucleus level of γH2A.X. Moreover, caspase inhibitor Z-VAD and ROS generation inhibitor N-acetyl-L-cysteine (NAC) attenuated the isoflurane-induced increase in γH2A.X level. However, NAC did not significantly alter the isoflurane-induced reduction in p53 level. Finally, p53 activator (actinomycin D) and inhibitor (pifithrin-α) attenuated and potentiated the isoflurane-induced increase in γH2A.X level, respectively. These findings suggest that isoflurane might induce DNA damage, as represented by increased γH2A.X level, via induction of oxidative stress and inhibition of the repair of DNA damage through the p53 signaling pathway.

Section: Methodsmentioning

confidence: 99%

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Self Cite

“…The FCT was performed as described by Zhang et al [20,21] with modifications. The training in FCT (XR-XC404, Shanghai Xin Soft Information Technology Co. Ltd.) was performed as follows.…”

Section: Fear Conditioning Test (Fct)mentioning

confidence: 99%

“…After the context test, each mouse was placed for 390 s in a novel chamber altered in shape, color, and smell. The same tone was presented for another 180 s without the foot shock to evaluate hippocampusindependent memory [20,22]. Cognitive deficits in the test was assessed by measuring the amount of time the mouse demonstrated "freezing behavior," which is defined as a completely immobile posture except for respiratory efforts.…”

Section: Fear Conditioning Test (Fct)mentioning

confidence: 99%

Mitochondria-Targeted Peptide Reverses Mitochondrial Dysfunction and Cognitive Deficits in Sepsis-Associated Encephalopathy

Zhang

Hao

et al. 2014

Sepsis-associated encephalopathy (SAE) is associated with increased mortality, morbidity, and long-term cognitive impairments. Its pathophysiology remains to be determined and an effective pharmacologic treatment is lacking. The goal of this study was to investigate the effects of the mitochondria-targeted peptide SS-31 on mitochondrial function and cognitive deficits in SAE mice. C57BL/6 male mice were randomly divided into sham, sham + SS-31, cecal ligation and puncture (CLP), and CLP + SS-31 groups. Peptide SS-31 (5 mg/kg) was intraperitoneally administrated immediately after operation and afterwards once daily for six consecutive days. Surviving mice were subjected to behavioral tests and the hippocampus was collected for biochemical analysis 7 days after operation. The results showed that CLP resulted in high mortality rate and cognitive deficits, representative characteristics of SAE. A physiological mechanistic investigation revealed that mitochondrial function of hippocampus was severely impaired, coupled with reactive oxygen species (ROS) generation, triggering neuronal apoptosis and inflammation. Notably, administration of peptide SS-31 protected the integrity of mitochondria, reversed the mitochondrial dysfunction, inhibited the apoptosis resulting from the release of cytochrome c, diminished the response of inflammation, and ultimately reversed the behavior deficits in the SAE mice. In conclusion, our data demonstrate that daily treatment with mitochondria-targeted peptide SS-31 reduces mortality rate and ameliorates cognitive deficits, which is possibly through a mechanism of reversing mitochondrial dysfunction and partial inhibition of neuronal apoptosis and inflammation in the hippocampus of the SAE mice.

“…Several lines of evidence from animal studies suggest the clinically relevant concentration of sevoflurane exposure can induce robust neuroapoptosis in the neonatal brain and cause subsequent long-term neurobehavioral abnormalities later in life [1][2][3][4]. Several mechanisms, including the compromise of mitochondrial integrity and neuroapoptosis [5], a decrease in the brainderived neurotrophic factor [6], the enhancing of gammaaminobutyric acid type A receptor-mediated excitation [7], an increase in the levels of stress hormones [8], activation of the inflammatory signaling pathways [9], and inhibition of neurogenesis [10] have been proposed, but the mechanisms underlying sevoflurane-induced neurocognitive impairment remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

Wang

Sun

et al. 2016

Parvalbumin (PV) interneurons are critically involved in the cognitive processes. Based on prior investigations that environmental enrichment reverses impaired cognition after anesthetic exposure, we proposed that environmental enrichment protects PV interneurons and thereby improves sevoflurane-induced cognitive impairments. Six-day-old C57BL/6 male mice were exposed to 3 % sevoflurane or 30 % oxygen/air 2 h daily for 3 days from postnatal day 6 (P6) to P8. The mice were randomly allocated to an enriched environment for 2 h daily between P8 and P90 or a standard environment. Western blotting and immunofluorescence were used for determining PV expression in the prefrontal cortex and hippocampus. In another set of experiments, cognitive tests were assessed by the open field test (P41), Morris water maze test (P54-60), and fear conditioning tests (P42-43 and P89-90). Exposure of neonatal mice to sevoflurane resulted in a reduced freezing response in the contextual test at P43 but not P90. The PV expression in these mice was decreased at P9, P14, P28, and P42, but not at ≥P60. No colocalization of caspase-3 and 5-bromo-2-deoxyuridine or caspase-3 and PV was observed, suggesting that caspase-independent pathways may be involved in the mediation of sevoflurane-induced down-regulation of PV. The sevoflurane-exposed mice that were placed in an enriched environment exhibited normal behavior and had PV interneurons that did not differ from those in the control mice at P42-43. Neonatal sevoflurane exposure induces a reduced freezing response in the contextual test at P43 and developmental delays in PV interneurons in the prefrontal cortex and hippocampus. Placement of the sevoflurane-exposed mice in an enriched environment can prevent these abnormalities.