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Anesthetic Ketamine-Induced DNA Damage in Different Cell Types In Vivo
Daniela Dimer Leffa1, Bruno Nunes Bristot2, Adriani Paganini Damiani2
1Laboratory of Molecular and Cellular Biology, Graduate Program of Health Sciences, Department of Health Sciences, University of Southern Santa Catarina, UNESC, 1105, Universitária Rd, 88806000, Criciúma, SC, Brazil. daniela_leffa@hotmail.com.
Abstract:
The use of a combination of ketamine and xylazine is broadly used either for anesthesia or euthanasia in rodent animal models in research. However, the genotoxicity and mutagenic effects of these drugs are unknown. Therefore, the aim of this study was to evaluate these effects to help the understanding of elevated values in negative controls in genotoxic/mutagenic assays. Sixty CF-1 mice were divided into ten groups of six mice per group: negative control (saline), positive control (doxorubicin, 40 mg/kg), ketamine at 80 mg/kg and xylazine at 10 mg/kg, ketamine at 100 mg/kg and xylazine at 10 mg/kg, ketamine at 140 mg/kg and xylazine at 8 mg/kg, ketamine at 80 mg/kg, ketamine at 100 mg/kg, ketamine at 140 mg/kg, xylazine at 8 mg/kg, and xylazine at 10 mg/kg. After drug induction, the blood cells were analyzed at 1, 12, and 24 h by the comet assay, while the brain cortex, liver, and kidney cells were verified just at 24 h by the comet assay and bone marrow was tested at 24 h by micronucleus test. The positive control was significantly different in relation to the negative control in all times and tissue analyzed. The dose of ketamine at 140 mg/kg plus xylazine at 8 mg/kg and only ketamine at 140 mg/kg exhibited a genotoxic effect in blood and brain cells at all the times analyzed. The doses of ketamine at 80 and 100 mg/kg in association or not with xylazine showed increased DNA damage at 1 and 12 h, but this effect was reversed after 24 h of drug administration. The liver, kidney, and bone marrow cells of animals treated with ketamine or xylazine isolated or combined did not differ when compared with the negative control. Then, our findings emphasize the necessity of more studies that prove safety of the ketamine use, since that anesthetic can be able to induce false-negative results in genotoxic experimental studies.
Insights
Ketamine and xylazine, commonly used anesthetics in research rodents, may cause genotoxicity. High doses of ketamine alone or with xylazine induced DNA damage, potentially affecting genotoxic assay results.
Area of Science:
- Toxicology
- Genetics
- Animal Research
Background:
- Ketamine and xylazine are widely used for anesthesia and euthanasia in rodent research models.
- The genotoxicity and mutagenic potential of these commonly used drugs remain largely uncharacterized.
- Understanding these effects is crucial for interpreting results in genotoxic and mutagenic assays, particularly concerning elevated values in negative controls.
Purpose of the Study:
- To evaluate the genotoxic and mutagenic effects of ketamine and xylazine, individually and in combination, in CF-1 mice.
- To determine if ketamine and xylazine administration can lead to DNA damage in various tissues.
- To provide data that aids in the understanding of potential false-negative or false-positive results in genotoxicity studies using these anesthetics.
Main Methods:
- Sixty CF-1 mice were divided into ten groups, receiving saline (negative control), doxorubicin (positive control), various doses of ketamine and xylazine alone or in combination.
- Blood cells were analyzed at 1, 12, and 24 hours post-administration using the comet assay.
- Brain cortex, liver, kidney cells were analyzed at 24 hours by comet assay, and bone marrow by the micronucleus test.
Main Results:
- The positive control (doxorubicin) showed significant genotoxicity across all tested times and tissues.
- Ketamine (140 mg/kg) combined with xylazine (8 mg/kg), and ketamine (140 mg/kg) alone, demonstrated genotoxic effects in blood and brain cells at all time points.
- Lower doses of ketamine (80-100 mg/kg), with or without xylazine, induced transient DNA damage at 1 and 12 hours, which resolved by 24 hours. No genotoxicity was observed in liver, kidney, or bone marrow.
Conclusions:
- High-dose ketamine, particularly when combined with xylazine, exhibits genotoxic potential in rodent blood and brain cells.
- The transient DNA damage observed with lower ketamine doses may lead to confounding results in genotoxicity assays.
- Further research is necessary to fully elucidate the safety profile of ketamine, as its use may impact the reliability of genotoxic experimental outcomes.
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