New synthetic monophenolic antioxidant TS-13 penetrates the blood-brain barrier

TS-13 (sodium 3-(3’-tert-butyl-4’-hydroxyphenyl)propylthiosulfonate) is a synthetic antioxidant that has demonstrated biological effectiveness in numerous studies in modeling pathological conditions in vivo, in particular, in the model of Parkinson’s disease. In order to establish whether these effects are mediated or associated, among other things, with the direct effect of TS-13 on the organs and tissues of animals, in this work, the concentration of TS-13 in rat blood plasma and brain after intragastric administration was determined. Material and methods. After a single intragastric administration of a solution of TS-13 at a dose of 100 mg/kg, biomaterial (blood, brain) was taken for 24 h in male Sprague Dawley stock rats (n = 57). To measure the concentration of a substance in samples, a bioanalytical method was developed and validated using high-performance liquid chromatography with UV detection. Results and discussion. The method of quantitative determination was developed by us for the first time and validated before the study. It has been established that the calculated values of the calibration samples meet the acceptance criteria (have the required accuracy and precision) in the concentration range from 0.05 to 6 µg/ml, R=0.9998. The results of determining TS-13 concentration in rat blood plasma and brain showed that after a single administration per os, the compound enters the blood, where it is detected for 15 h (mean retention time 7.94 h, half-life 7.59 h, elimination constant 0.13 h-1, total clearance 40.1 l/(kg × h)), and also penetrates the blood-brain barrier, quickly entering the brain (maximum concentration is reached after 1 h). The compound has a low affinity for brain tissue (tissue availability 0.32), and therefore its concentration does not reach high values, however, a slow excretion of the substance is observed - the average retention time is 6.56 h, the half-life is 6.43 h, the elimination constant 0.11 h-1. Conclusions. After a single intragastric administration to rats, TS-13 enters the blood, where at least part of it is detected unchanged after 30 minutes, reaching maximum values after 1 hour. Similar kinetics of the substance is characteristic of the brain, where it is found in smaller amounts. Thus, as a result of the study, it was shown that TS-13 penetrates the blood-brain barrier and is able to directly affect brain structures, which, however, does not negate the possibility of an indirect effect mediated by the ability to change the activity of intra- and intercellular signaling systems.

1. Zenkov N.K., Menshchikova E.B., Kandalintseva N.V., Oleynik A.S., Prosenko A.E., Gusachenko O.N., Shklyaeva O.A., Vavilin V.A., Lyakhovich V.V. Antioxidant and antiinflammatory activity of new water-soluble sulfur-containing phenolic compounds. Biochemistry (Mosc.). 2007;72(6):644–651. doi: 10.1134/S0006297907060077

2. Gainutdinov P.I., Kozhin P.M., Chechushkov A.V., Martinovich G.G., Kholshin S.V., Kandalintseva N.V., Zenkov N.K., Menshchikova E.B. Inverse relationship between the antioxidant activity of structurally related synthetic monophenols and their toxicity to tumor cells. Sibirskij nauchnyj medicinskij zhurnal = Siberian Scientific Medical Journal. 2018;38(1):22–31. [In Russian]. doi: 10.15372/SSMJ20180104

3. Menshchikova E.B., Zenkov N.K., Weisman N.Y., Kandalintseva N.V., Prosenko A.E. Effect of phenol inducing the antioxidant responsive element on Drosophila melanogaster lifespan. Bull. Exp. Biol. Med. 2010;150(1):65–67. doi: 10.1007/s10517-0101070-5

4. Menshchikova E.B., Wisman N.Y., Zenkov N.K., Tkachev V.O., Kandalintseva N.V. ARE-inducing phenol antioxidant TS-13 improves survival of Drosophila melanogaster in oxidative stress. Bull. Exp. Biol. Med. 2012;154(2):260–264. doi: 10.1007/s10517012-1926-y

5. Menshchikova E., Tkachev V., Lemza A., Sharkova T., Kandalintseva N., Vavilin V., Safronova O., Zenkov N. Water-soluble phenol TS-13 combats acute but not chronic inflammation. Inflamm. Res. 2014;63(9):729–740. doi: 10.1007/s00011-014-0746-0

6. Menshchikova E.B., Zenkov N.K., Kozhin P.M., Chechushkov A.V., Kovner A.V., Khrapova M.V., Kandalintseva N.V., Martinovich G.G. Synthetic phenolic antioxidant TS-13 suppresses the growth of Lewis lung carcinoma and potentiates oncolytic effect of doxorubicin. Bull. Exp. Biol. Med. 2019;166(5):646– 650. doi: 10.1007/s10517-019-04410-6

7. Menshchikova E.B., Khrapova M.V., Kozhin P.M., Chechushkov A.V., Serykh A.E., Romakh L.P., Kandalintseva N.V. Protective effect of a new monophenolic antioxidant TS-13 in a mouse model of Parkinson’s disease. Bull. Exp. Biol. Med. 2023;175(2):233–238. doi: 10.1007/s10517-02305847-6

8. Khrapova M.V., Chechushkov A.V., Kozhin P.M., Romakh L.P., Serykh A.E., Kholshin S.V., Kandalintseva N.V., Menshchikova E.B. The toxicity of a new monophenolic synthetic inducer of Keap1/ Nrf2/ARE redox-sensitive signaling system in vitro and in vivo. Cell Tissue Biol. 2023;17(3):299–305. doi: 10.1134/S1990519X23030069

9. Oleynik A.S., Kuprina T.S., Pevneva N.Y., Markov A.F., Kandalintseva N.V., Prosenko A.E., Grigoriev I.A. Synthesis and antioxidant properties of sodium S-[3-(hydroxyaryl)propyl] thiosulfates and [3-(hydroxyaryl)propane]-1-sulfonates. Russian Chemical Bulletin. 2007;58(6):1135–1143. doi: 10.1007/s11172007-0172-3

10. Manual for laboratory animals and alternative models in biomedical technologies. Eds. N.N. Karkishchenko, S.V. Grachev. Moscow: Profil, 2010. 358 p. [In Russian].

11. Guidelines for pre-clinical drug research. Ed. A.N. Mironov. Pt. 1. Moscow: Grif i K, 2012. 944 p. [In Russian].

12. Miroshnichenko I.I. Basics of pharmacokinetics. Moscow: GEOTAR-MED, 2002. 192 p. [In Russian].

13. General pharmacopoeia article 1.1.0012.15. Validation of analytical methods. In: State Pharmacopoeia of the Russian Federation. XIV edition. Vol. 1. Moscow, 2018. 276. [In Russian].