Anesthetic Ketamine-Induced DNA Damage in Different Cell Types In Vivo

Leffa, Daniela Dimer; Bristot, Bruno N.; Damiani, Adriani Paganini; Borges, Gabriela Daminelli; Daumann, Francine; Zambon, Gabriela Maria; Fagundes, Gabriela Elibio; Andrade, Vanessa Moraes de

doi:10.1007/s12035-015-9476-8

Cited by 18 publications

(9 citation statements)

References 45 publications

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“…The negative findings could be due to the very low concentration of isoflurane to which the people were exposed. Employing comet assay and micronucleus test, Leffa et al demonstrated that anesthetic ketamine with and without xylazine could induce DNA damage in blood and brain cells of mice [66]. However, the dose of ketamine used in the experiment was not clinically relevant (140 mg/kg) [66].…”

Section: Discussionmentioning

confidence: 99%

“…Employing comet assay and micronucleus test, Leffa et al demonstrated that anesthetic ketamine with and without xylazine could induce DNA damage in blood and brain cells of mice [66]. However, the dose of ketamine used in the experiment was not clinically relevant (140 mg/kg) [66]. In the current studies, we used a clinically relevant concentration of isoflurane (2 %) and found that the treatment with a clinically relevant concentration of isoflurane was able to induce DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Mol Neurobiol

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Mol Neurobiol

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“…10E). Doxorubicin is commonly used as a positive control for comet assays because it is recognized for causing DNA damaging [59][60][61]. It is important to highlight that although significant DNA damage has been observed in the highest dose, the DNA damage in the cells (nucleoids) was predominantly minor (class 1 -data not shown), with only a few cells showing a large amount of damage (classes 2 and 3).…”

Section: In Vivo Assaysmentioning

confidence: 99%

The trans -[Ru(PPh 3 ) 2 ( N , N -dimethyl- N ′-thiophenylthioureato-k 2 O,S)(bipy)]PF 6 complex has pro-apoptotic effects on triple negative breast cancer cells and presents low toxicity in vivo

Becceneri

Popolin

Plutı́n

et al. 2018

Journal of Inorganic Biochemistry

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Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh)(N,N-dibutyl-N'-benzoylthioureato-kO,S)(2,2'-bipyridine (bipy))]PF(1), trans-[Ru(PPh)(N,N-dimethyl-N'-thiophenylthioureato-kO,S)(bipy)]PF(2) and trans-[Ru(PPh)(N,N-dimethyl-N'-benzoylthioureato-kO,S)(bipy)]PF(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice.

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“…Liu et al (2013) and Kristin et al (2003) add that a high dose of ketamine can influence genotoxicity in the blood cells and brain cortex of mice. DNA damage continually occurs 24 hours after the administration of anesthetic ketamine (Leffa et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Ketamine is a selective NMDA receptor inhibitor that works by decreasing calcium influx and brain injury (Zhang et al, 2007). Ketamine is sometimes combined with alpha-2 agonists, specifically xylazine (Leffa et al, 2015). Xylazine hydrochloride can act as an analgesic, sedative, and muscle relaxant (Gonca, 2015).…”

Section: Introductionmentioning

confidence: 99%

P53 expression in ischemic rat models after the administration of ketamine and ketamine-xylazine

et al. 2020

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Ketamine and ketamine-xylazine are often used as anesthetic drugs in animal models of ischemia. However, their neuroprotective and neurotoxic effects in ischemic animal models that have undergone tBCCAO are still under debate. The protein p53 is a pro-apoptotic factor involved in the cellular mechanism of ischemia. The interaction between death-associated protein kinase 1 (DAPK 1) and p53 is fundamental in determining whether cells experience necrosis or apoptosis in an ischemic stroke. This study was purposed to identify the presence or absence of differences between the p53 expressions in the brains of tBCCAO-induced ischemic rat models after the administration of ketamine and ketamine-xylazine. It employed a post-test control group design with four groups of adult male Wistar rats as the subject: (1) sham group operated with ketamine, (2) sham group operated with ketamine-xylazine, (3) models of tBCCAO-induced ischemia with ketamine, and (4) models of tBCCAO-induced ischemia with ketamine-xylazine. Ketamine was administered at the dose of 75mg/kg BW, while xylazine was at 8 mg/kg BW. The expression of p53 in rat brains was assessed by semi-quantification, specifically IHC staining with anti-p53 antibodies. P53 expression appeared as brownish stains in the cytoplasm of forebrain pyramidal neurons, and in this study, it was measured using the Allred score. The ANOVA test yielded a p-value of >0.05, implying the absence of difference between the p53 expressions in the brains of tBCCAO-induced ischemic rat models receiving ketamine and ketamine-xylazine.

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Anesthetic Ketamine-Induced DNA Damage in Different Cell Types In Vivo

Cited by 18 publications

References 45 publications

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

The trans -[Ru(PPh 3 ) 2 ( N , N -dimethyl- N ′-thiophenylthioureato-k 2 O,S)(bipy)]PF 6 complex has pro-apoptotic effects on triple negative breast cancer cells and presents low toxicity in vivo

P53 expression in ischemic rat models after the administration of ketamine and ketamine-xylazine

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