Regulation of ABCB1 Protein Function in the Cerebral Cortex with the Underlying Global Cerebral Ischemia

Abstract

INTRODUCTION: ABCB1 is a membrane transporter protein responsible for efflux of a wide range of drugs from cells. The study of the mechanisms of regulation of the functioning of ABCB1 protein in the brain in its ischemia will permit to propose new approaches to pharmacotherapy of cerebral ischemic pathology. AIM: To study the regulation of ABCB1 protein function in the cerebral cortex of rats with global cerebral ischemia. MATERIALS AND METHODS: The experiment was performed on 30 male rats with global cerebral ischemia modeled by bilateral occlusion of the common carotid arteries. The amount of ABCB1 protein and Nrf2 and HIF-1α transcription factors in the cerebral cortex was determined by enzyme immunoassay. The free radical status of the cerebral cortex was assessed by the concentration of malondialdehyde, SH groups, and by glutathione peroxidase (G-per) activity. RESULTS: Bilateral occlusion of the common carotid arteries caused an increase in the level of ABCB1 protein in the cerebral cortex of rats by the 4th hour of ischemia; in 24 hours it remained elevated, and in 72 hours decreased to values that did not differ from those of falsely operated rats. The content of malondialdehyde in the cerebral cortex increased in 2 and 4 hours after occlusion and then gradually decreased to the initial values. In 30 minutes and 4 hours after ischemia modeling, G-per activity decreased compared to the control values. The content of Nrf2 in the cerebral cortex increased in 2 and 4 hours after occlusion, then slightly decreased on the next day, and reached the initial values on the 3rd day of the experiment. The amount of HIF-1α increased only in 24 and 72 hours after the surgery. CONCLUSION: The amount of ABCB1 protein in the cerebral cortex of rats with global cerebral ischemia depends on the severity of oxidative stress, with Nrf2 and HIF-1α transcription factors playing a role in its regulation. Reduction of the amount of the transporter in the blood-brain barrier through the influence on the lipid peroxidation processes or synthesis of the studied transcription factors expands the possibilities of using ABCB1 protein substrates for improving the effectiveness of pharmacotherapy of diseases of the central nervous system.