Inhibition of ABCB1 activity in cerebrovascular disease may increase pharmacotherapy effectiveness

Abstract

Introduction. Despite the development of numerous drugs with neuroprotective activity, their efficacy in cerebrovascular disease remains low, which may partly be due to the efflux function of protein ABCB1 and insufficient penetration of the blood-brain barrier by these drugs.

Aim — to evaluate the potential to inhibit ABCB1 functional activity in the blood-brain barrier to improve the efficacy of neuroprotective therapy against brain ischemia.

Materials and methods. An experimental study was performed on 60 adult male Wistar rats split up into 5 groups: group 1 with falsely operated animals; group 2 with rats with modeled cerebral ischemia using bilateral ligation of the common carotid arteries and preliminary intravenous injection of saline (control ischemia); group 3 with animals that were intravenously administered a neuroprotective agent, an АВСВ1 substrate (nimodipine), 30 min before arterial ligation; group 4 with rats that were intravenously administered an АВСВ1 inhibitor (omeprazole) 30 minutes before disease modeling; and group 5 with animals with ischemia that were intravenously administered nimodipine together with omeprazole before the operation. The efficacy of the tested substances was based on a reduction in animal deaths and the severity of neurological deficits 4, 12, 24, 48, and 72 hours after pathology modeling.

Results. The combination of nimodipine and omeprazole increased rat survival after ischemia modeling and decreased neurological deficits compared with the control rats with cerebral ischemia and the rats administered a neuroprotective agent.

Conclusion. The combination of a neuroprotective agent (ABCB1 substrate) and a transporter inhibitor provides an effective approach to improve the efficacy of neuroprotective pharmacotherapy in cerebral ischemia.

For citation: Chernykh I.V., Shchulkin A.V., Pravkin S.K., Gatsanoga M.V., Yakusheva E.N. [Inhibition of ABCB1 activity in cerebrovascular disease may increase pharmacotherapy effectiveness]. Annals of clinical and experimental neurology. 2021; 15(1): 65–70. (In Russ.) https://doi.org/10.25692/ACEN.2021.1.8

About the authors

Ivan V. Chernykh

Ryazan State Medical University, Ryazan

Author for correspondence.
Email: platonova@neurology.ru
Russian Federation

Aleksey V. Shchulkin

Ryazan State Medical University, Ryazan

Email: platonova@neurology.ru
Russian Federation

Sergei K. Pravkin

Ryazan State Medical University, Ryazan

Email: platonova@neurology.ru
Russian Federation

Maria V. Gatsanoga

Ryazan State Medical University, Ryazan

Email: platonova@neurology.ru
Russian Federation

Elena N. Yakusheva

Ryazan State Medical University, Ryazan

Email: platonova@neurology.ru
Russian Federation

References

  1. Chernykh I.V., Shchulkin A.V., Gatsanoga M.V. et al. [Functional activity of P-glycoprotein with underlying brain ischemia]. Nauka molodykh (Eruditio Juvenium). 2019; 7(1): 46–52. doi: 10.23888/hmj20197146-52. (In Russ.)
  2. Schlachetzki F., Pardridge W.M. P-glycoprotein and caveolin-1alpha in endothelium and astrocytes of primate brain. Neuroreport. 2003; 14(16): 2041–2046. doi: 10.1097/00001756-200311140-00007. PMID: 14600494.
  3. Yakusheva E.N., Titov D.S. Structure and function of multidrug resistance protein 1. Biochemistry (Mosc). 2018; 83(8): 907–929. doi: 10.1134/S0006297918080047. PMID: 30208829.
  4. Spudich A., Kilic E., Xing H. et al. Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia. Nat Neurosci. 2006; 9: 487–488. doi: 10.1038/nn1676. PMID: 16565717.
  5. Ding Z.J., Li D., Chen X. et al. Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. Cancer Res Clin Oncol. 2010; 136(11): 1697–1707. doi: 10.1007/s00432-010-0828-5. PMID: 20217131.
  6. Tallis S., Caltana L.R., Souto P.A. et al. Changes in CNS cells in hyperammonemic portal hypertensive rats. J Neurochem. 2014; 128(3): 431–444. doi: 10.1111/jnc.12458. PMID: 24382264.
  7. Yakusheva E.N., Chernykh I.V. [The influence of experimental subacute hypobaric hypoxia on P-glycoprotein functional activity]. Rossiyskiy mediko-biologicheskiy vestnik imeni akademika I.P. Pavlova. 2013; 21(1): 60–64. (In Russ.)
  8. Tyurenkov I.N., Volotova E.V., Kurkin D.V. et al. [Neuroprotective and antioxidant effects of neuroglutam in cerebral ischemia]. Bull Exp Biol Med. 2015; 159(3): 365–367. DOI: 10.1007/ s10517-015-2964-z. PMID: 26212811.
  9. Wang X., Wang C., Yang Y., Bosn J. Ni. New monocyte locomotion inhibitory factor analogs protect against cerebral ischemia–reperfusion injury in rats. J Basic Med Sci. 2017; 17(3): 221–227. doi: 10.17305/bjbms.2017.1622. PMID: 28273031.
  10. Shan Y., Igbal Z., Ahmad L. et al. Effect of omeprazole on the pharmacokinetics of rosuvastatin in healthy male volunteers. Am J Therapeutics. 2016; 23(6): 1514–1523. doi: 10.1097/MJT.0000000000000221. PMID: 25719441.
  11. Ivashev M.N., Arl't A.V., Savenko I.A. et al. [Features of cardiohaemodynamics after usage ofzoletil at laboratory animals]. Nauchnyye vedomosti Belgorodskogo gosudarstvennogo universiteta. 2012; 123(4): 168–171. (In Russ.)
  12. Kurkin D.V., Volotova E.V., Bakulin D.A. et al. [Influence of chloral hydrate anesthesia on the survival of experimental rats with bilateral common carotid artery occlusion]. Sovremennyye problemy nauki i obrazovaniya. 2017; (1). URL: http://www.science-education.ru/ru/article/view?id=26056. (In Russ.)
  13. Yamamoto M., Shina T., Vozumi T. et al. A possible role of a lipid peroxidation in cellular damage, caused by cerebral ischemia and the protective effect of α-tocopherol administration. Stroke. 1983; (14): 977–982. doi: 10.1161/01.str.14.6.977. PMID: 6659003.
  14. Gannushkina I.V. [Cerebral circulation in different types of circulatory hypoxia of the brain]. Vestnik Rossiyskoy Akademii meditsinskikh nauk. 2000; (9): 22–27. (In Russ.)
  15. Farkas E., Luiten P.G.M., Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev. 2007; 54(1): 162–180. doi: 10.1016/j.brainresrev.2007.01.003. PMID: 17296232.
  16. Mazina N.V., Volotova E.V., Kurkin D.V. [Neuroprotective effect of the new derivative GABA-RGPU-195 in cerebral ischemia]. Fundamental'nyye issledovaniya. 2013; (6): 1473–1476. (In Russ.)
  17. Barar J., Rafi M.A., Pourseif M.M., Omidi Y. Blood-brain barrier transport machineries and targeted therapy of brain diseases. Bioimpacts. 2016; 6(4): 225–248. doi: 10.15171/bi.2016.30. PMID: 28265539.
  18. Comerford K.M., Wallace T.J., Karhausen J. et al. Hypoxia-inducible Factor-1-dependent Regulation of the Multidrug Resistance (MDR1) Gene. Cancer Res. 2002; 62: 3387. PMID: 12067980.
  19. Wang F., Ji S., Wang M. et al. HMGB1 promoted P-glycoprotein at the blood-brain barrier in MCAO rats via TLR4/NF-κB signaling pathway. Eur J Pharmacol. 2020; 880: 173189. doi: 10.1016/j.ejphar.2020.173189. PMID: 32417325.
  20. Chernykh I.V., Yakusheva E.N., Shchulkin A.V. et al. [P-glycoprotein expression in blood-brain barrier in bilateral occlusion of the common carotid artery]. Nauchnyye vedomosti Belgorodskogo gosudarstvennogo universiteta. 2015; 29(4): 91–95. (In Russ.)
  21. Tournier N., Goutal S., Auvity S. et al. Strategies to inhibit ABCB1- and ABCG2-mediated efflux transport of erlotinib at the blood-brain barrier: a PET study on nonhuman primates. J Nucl Med. 2017; 58(1): 117–122. doi: 10.2967/jnumed.116.178665. PMID: 27493269.
  22. Cannon R.E, Peart J.C., Hawkins B.T. et al. Targeting blood–brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci USA. 2012; 109(39): 15930–15935. doi: 10.1073/pnas.1203534109. PMID: 22949658.
  23. O'Brien F.E., Dinan T.G., Griffin B.T. et al. Interactions between antidepressants and P-glycoprotein at the blood–brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol. 2012; 165(2): 289–312. doi: 10.1111/j.1476-5381.2011.01557.x. PMID: 21718296.
  24. Hu M., Liu Z., Lv P. et al. Autophagy and Akt/CREB signalling play an important role in the neuroprotective effect of nimodipine in a rat model of vascular dementia. Behav Brain Res. 2017; 325(A): 79−86. doi: 10.1016/j.bbr.2016.11.053. PMID: 27923588.

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Copyright (c) 2021 Chernykh I.V., Shchulkin A.V., Pravkin S.K., Gatsanoga M.V., Yakusheva E.N.

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