Investigation of the effects of HİGH cell penetration and mitochondrial targeted antioxidants on chemotherapy-induced peripheral neuropathy in vitro model

Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological complication that develops as a result of damage to the peripheral nervous system by cancer chemotherapy, negatively affects the quality of life of patients, often causes sensory disturbances, and requires dose restriction. It is a side effect that causes delay and/or interruption of treatment in cancer patients receiving chemotherapy and significantly affects the patient's quality of life. Its pathophysiology is still not fully understood, and it is thought that oxidative damage, ion channel activity changes and mitochondrial dysfunction play a role in the development of neuropathy. Data on prevention and treatment are limited. The only agent with proven efficacy is duloxetine. In this thesis, it was aimed to evaluate the effects of daidzein, MnTBAP chloride and Mito-TEMPO, which are mitochondria-targeted antioxidants with high cell penetration and have not been tested for this purpose before, on CIPN. Materials and Methods: Neuropathy development (on cell viability) was investigated by simultaneous application with different doses of antineoplastic agents cisplatin, paclitaxel, vincristine and mitochondria-targeted antioxidants daidzein, MnTBAP chloride, Mito-TEMPO applied in to cell cultures obtained from dorsal root ganglion (DRG) sensory neurons of adult rats. Neurotoxicity analyzes were performed by evaluating the viability of DRG neurons by xCELLigence real-time cell analysis. Each experiment was repeated with an E-plate containing 3 different (isolated from individual animals) cultures. Results: Cell index values of the wells in the e-plates were monitored in the xCELLigence RTCA system at 15-minute intervals up to 24 hours. At the end of the 24th hour, there was a statistically significant decrease in cell index values in all wells in which only antineoplastic agent (cisplatin 0.01 μM, 0.1 μM; paclitaxel 0.01 μM, 1 μM; vincristine 0.01 μM, 1 μM) was added. It was observed that all doses of antineoplastics used had a statistically significant neurotoxic effect (p:0.0050, p:0.00161, p:0.00514, p:0.02605, p:0.00644, p:0.00667, respectively). There was no significant difference between the antineoplastic agents in the severity of the developing neurotoxicity. Daidzein (10 μM, 30 μM and 100 μM), MnTBAP chloride (60 μM, 100 μM ve 200 μM), and Mito-TEMPO (30 μM, 100 μM and 200 μM) applied to the wells in the presence of cisplatin (0.01 μM and 0.1 μM), paclitaxel (0.01 μM and 1 μM), and vincristine (0.01 μM) failed to significantly prevent cell index reduction caused by antineoplastic agents. Daidzein (10 μM, 30 μM, and 100 μM) applied to the wells in the presence of 1 μM vincristine was not effective in reducing vincristine-induced cell index reduction. 60 μM, 100 μM and 200 μM doses of MnTBAP chloride and 200 μM doses of Mito-TEMPO added to the wells after 1 μM vincristine increased the cell index values in the wells and statistically significantly reduced the cell index decrease caused by vincristine (p:0,01008, p:0.03386, p:0.03115, p:0.0378, respectively). There was no statistically significant difference between the doses in terms of protective efficacy. The 30 μM and 100 μM doses of Mito-TEMPO could not prevent vincristine-induced cell index reduction. Conclusion: In this study, it was observed that cisplatin, paclitaxel and vincristine were associated with the development of neurotoxicity as stated in the literature. Although daidzein, MnTBAP chloride and Mito-TEMPO were shown to have neuroprotective effects in DRG neuron culture studies, it was thought that the lack of similar effects in this study may be due to the severe neurodegenerative effects of antineoplastic agents on neurons. Considering the lack of studies evaluating the effects of these antioxidants on CIPN in the literature, more studies are needed on this subject.