Modulatory effect of curcumin on ketamine-induced toxicity in rat thymocytes: Involvement of reactive oxygen species pathway

• Published in: Bosnian journal of basic medical sciences 2018-11, Vol.18 (4), p.320
• Main Authors: Pavlovic, Svetlana, Jovic, Zorica, Karan, Radmila, K, Rankovic, Gorana, Golubovic, Mladjan, Lilic, Jelena, Pavlovic, Voja
• Format: Article
• Language: English
• Subjects: Care and treatment; Complications and side effects; Development and progression; Drugs; Health aspects; Ketamine; Nervous system diseases; Physiological aspects; Protein kinases; Reactive oxygen species; Risk factors; Thymus; Turmeric
• ISSN: 1512-8601
• DOI: 10.17305/bjbms.2018.2607

Ketamine is a widely used anesthetic in pediatric clinical practice. Previous studies have demonstrated that ketamine induces neurotoxicity and has a modulatory effect on the cells of the immune system. Here, we evaluated the potential protective effect and underlying mechanisms of natural phenolic compound curcumin against ketamine-induced toxicity in rat thymocytes. Rat thymocytes were exposed to 100 [micro]M ketamine alone or combined with increasing concentrations of curcumin (0.3, 1, and 3 [micro]M) for 24 hours. Cell viability was analyzed with CCK-8 assay kit. Apoptosis was analyzed using flow cytometry and propidium iodide as well as Z-VAD-FMK and Z-LEHD-FMK inhibitors. Reactive oxygen species (ROS) production and mitochondrial membrane potential [MMP] were measured by flow cytometry. Colorimetric assay with DEVD-pNA substrate was used for assessing caspase-3 activity. Involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was tested with Wortmannin inhibitor. Ketamine induced toxicity in cells, increased the number of hypodiploid cells, caspase-3 activity and ROS production, and inhibited the MMP Co-incubation of higher concentrations of curcumin (1 and 3 [micro]M) with ketamine markedly decreased cytotoxicity, apoptosis rate, caspase-3 activity, and ROS production in rat thymocytes, and increased the MMP. Application of Z-VAD-FMK (a pan caspase inhibitor) or Z-LEHD-FMK (caspase-9 inhibitor) with ketamine effectively attenuated the ketamine-induced apoptosis in rat thymocytes. Administration of Wortmannin (a PI3K inhibitor) with curcumin and ketamine significantly decreased the protective effect of curcumin on rat thymocytes. Our results indicate that ketamine-induced toxicity in rat thymocytes mainly occurs through the mitochondria-mediated apoptotic pathway and that the PI3K/Akt signaling pathway is involved in the anti-apoptotic effect of curcumin. KEY WORDS: Ketamine; curcumin; toxicity; thymocytes; PI3K/Akt signaling pathway; anti-apoptotic effect; protective effect; apoptosis; reactive oxygen species DOI: