A method of inhibiting the ABCB1 protein in the blood-brain barrier in vivo

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Abstract

Introduction. Increased functional activity of the P-glycoprotein transporter (ABCB1) in the blood-brain barrier (BBB) is a possible reason why neuroprotective pharmacotherapy is ineffective after ischaemic stroke.

Study aim — to develop a way to inhibit the functional activity of ABCB1 at the BBB.

Materials and methods. The study was performed on 60 male Wistar rats weighing 200-280 g. The functional activity of ABCB1 at the BBB was assessed by measuring the plasma and cortical levels of the marker transporter substrate fexofenadine (intravenous administration of 10 mg/kg). Thirty minutes before the administration of fexofenadine, 1 ml/kg of intravenous saline (n = 30) or 17.6 mg/kg of omeprazole, the transporter's systemic inhibitor (n = 30), was administered to the rats. The total amount of fexofenadine in the systemic circulation and the cerebral cortex was assessed using high performance liquid chromatography, by calculating the area under the blood concentration–time curve (AUC0-t(plasma)) or the cerebral cortex concentration (AUC0-t(brain)). BBB permeability was calculated using the ratio AUC0-t(brain)/AUC0-t(plasma).

Results. The administration of omeprazole before fexofenadine did not affect the plasma level of the latter at any time point under analysis. Fexofenadine’s AUC0-t(plasma) also did not differ between the series. However, the administration of omeprazole increased the cortical level of fexofenadine by 2.96 times (p = 0.009), 5 minutes after administration of the latter, and increased the AUC0-t(brain) by 1.49 times (p = 0.012). AUC0-t(brain)/AUC0-t(plasma) increased by 1.71 times when omeprazole was used (p = 0.003). Therefore, omeprazole inhibits the functional activity of ABCB1 at the BBB.

Conclusions. We developed and tested a method for inhibiting ABCB1 activity at the BBB.

About the authors

Ivan V. Chernykh

Ryazan State Medical University

Email: ivchernykh88@mail.ru
ORCID iD: 0000-0002-5618-7607

Сand. Sci. (Biol), Head, Department of pharmaceutical chemistry

Russian Federation, Ryazan

Alexey V. Shchulkin

Ryazan State Medical University

Email: alekseyshulkin@rambler.ru
ORCID iD: 0000-0003-1688-0017

D. Sci. (Med), Associated Professor, Professor, Department of pharmacology

Russian Federation, Ryazan

Pavel Yu. Mylnikov

Ryazan State Medical University

Email: pavelmylnikov@mail.ru
ORCID iD: 0000-0001-7829-2494

Assistant, Department of pharmacology

Russian Federation, Ryazan

Ekaterina E. Kirichenko

Ryazan State Medical University

Author for correspondence.
Email: ekaterinakir2013@yandex.ru
ORCID iD: 0000-0003-3511-7033

Cand. Sci. (Biol.), Associated Professor, Department of pharmaceutical chemistry

Russian Federation, Ryazan

Maria V. Gatsanoga

Ryazan State Medical University

Email: mvgatsanoga@mail.ru
ORCID iD: 0000-0002-1116-6271

Cand. Sci. (Med), Assistant, Department of pharmacology

Russian Federation, Ryazan

Elena N. Yakusheva

Ryazan State Medical University

Email: e.yakusheva@rzgmu.ru
ORCID iD: 0000-0001-6887-4888

D. Sci. (Med), Professor, Head, Department of pharmacology

Russian Federation, Ryazan

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2. Fig. 1. Changes in the plasma fexofenadine level after intravenous administration of 10 mg/kg of fexofenadine to rats in the control group and in the group that received omeprazole (17.6 mg/kg intravenously).

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3. Fig. 2 Changes in the cortical fexofenadine level after intravenous admi- nistration of 10 mg/kg of fexofenadine to rats in the control group and in the group that received omeprazole (17.6 mg/kg intravenously).

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Copyright (c) 2022 Chernykh I.V., Shchulkin A.V., Mylnikov P.Y., Kirichenko E.E., Gatsanoga M.V., Yakusheva E.N.

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