Evaluation of ABCB1-protein inhibition prospectiveness in hematoencephalic barrier as method for increasing efficiency of pharmacotherapy in cerebral ischemia

The aim of the article is to evaluate the ABCB1 protein inhibition in the blood-brain barrier to increase the effectiveness of neuroprotective therapy for focal and global cerebral ischemia.

Materials and methods. The work was performed on 103 male Wistar rats. In the 1st group (n=33), the neuroprotective activity of the ABCB1 protein substrate, nimodipine (0.4 mg/kg), was analyzed in terms of reducing the area of the brain necrosis after a 1-hour occlusion of the middle cerebral artery with a 24-hour reperfusion (focal ischemia). In the 2nd group (n=60), the effectiveness of nimodipine was analyzed by reducing the lethality of rats and the neurological deficit (ND) level against the background of the bilateral occlusion of the common carotid arteries (global ischemia). In both groups, nimodipine was used alone or in the combination with omeprazole, the ABCB1 protein inhibitor (17.6 mg/kg). The drugs were administered intravenously.

Results. The nimodipine administration to the 1st group led to the reduction of the necrosis focus by 28% compared with the control series. Omeprazole did not cause a change in the area of the necrosis. The combination of drugs caused a decrease in the area of the necrosis in relation to the control by 29%; there were no differences in comparison with the nimodipine series. Nimodipine reduced the rats’ lethality in the 2nd group against the background of the pathology (a tendency). Omeprazole alone did not change the mortality. The drug combination reduced the mortality compared to the control and nimodipine series. The administration of omeprazole alone did not reduce the neurological deficit score relative to the control. In the nimodipine series, ND was 88% lower than the control, after 24 hours. With the administration of the drugs combination, this indicator decreased in relation to the control by 88%, 80%, 88%, 87% and 86% after 4, 12, 24, 48 and 72 hours, respectively, and in relation to the nimodipine series it decreased by 60% and 67% after 4 and 48 hours.

Conclusion. The ABCB1 protein inhibition is promising for increasing the effectiveness of neuroprotective therapy for global ischemia, but not for focal cerebral ischemia.

Abbreviations: BBB – blood-brain barrier; TTC – triphenyltetrazolium chloride; ATP – adenosine triphosphate; creb – cAMP response element-binding; Akt – protein kinase B (intracellular protein kinase B enzyme); IC50 – half-maximal (50%) inhibitory concentration.