Functional activity of p-glycoprotein in blood-brain barrier during experimental par-kinson's syndrome
- 作者: Chernykh I.1, Shchulkin A.1, Mylnikov P.1, Gatsanoga M.1, Gradinar M.1, Yesenina A.1, Yakusheva E.1
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隶属关系:
- Ryazan State Medical University
- 期: 卷 27, 编号 2 (2019)
- 页面: 150-159
- 栏目: Original study
- URL: https://journals.rcsi.science/pavlovj/article/view/14533
- DOI: https://doi.org/10.23888/PAVLOVJ2019272150-159
- ID: 14533
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详细
Background. P-glycoprotein (Pgp, ABCB1-protein) is a membrane transporter with broad substrate specificity that is localized in hepatocytes, enterocytes, epithelial renal tubules, and also in tissue barriers, including blood-brain barrier (BBB). Increased Pgp activity in BBB is one of the reasons for the pharmacoresistance of a number of CNS diseases.
Aim. Analysis of Pgp functional activity in BBB during experimental Parkinson's syndrome.
Materials and Methods. The work was performed on 90 Wistar rats, divided into 3 series (n=30 in each). The 1 series (control) was subcutaneously injected sunflower oil once a day for 7 days, and Pgp activity in BBB was assessed on the 8th day. The 2 and 3 series (pathology control) − were administered rotenone at a dose of 2.5 mg/kg once a day for 7 and 28 days respectively to simulate parkin-sonism. At the end of the experiment Pgp activity was estimated. To confirm Parkinson's syndrome, in addition to the clinical picture, level of dopamine in midbrain and striatum was determined using enzyme-linked immunosorbent assay. Pgp functional activity in BBB was assessed by the degree of penetration of its marker substrate fexofenadine into the brain after its intravenous administration at a dose of 10 mg/kg. The content of fexofenadine in the blood plasma and in brain tissue was estimated by the area under pharmacokinetic curve of the substance (in the blood or brain tissues) − AUC0-t(plasma) or AUC0-t(brain) respectively. To assess the BBB permeability the ratio AUC0-t(brain) / AUC0-t(plasma) was calculated.
Results. Rotenone administration led to the development of parkinsonism typical picture: muscle stiffness, hypokinesia, gait instability. There was a decrease in dopamine level in the striatum after 7 days by 69.6% (p=0.095), after 28 days − by 93.9% (p=0.008), in midbrain − by 72.7% (p=0.095) and 68.7% (p=0.032) respectively. Fexofenadine AUC0-t(plasma) and AUC0-t(brain) after its intravenous administration to control rats were 266.2 (246.4; 285.6) μg/ml*min and 5.9 (5.8;6.6) µg/g*min respectively, AUC0-t(brain) /AUC0-t(plasma) − 0.020 (0.019; 0.022). When rotenone was for 7 days administered − fexofenadine AUC0-t(brain) increased 2.02 times (p=0.0163), AUC0-t(brain) / AUC0-t(plasma) − 2.4 times (p=0.0283). 28 days administration of rotenone led to augmentation of AUC0-t(brain) of fexofenadine by 1.75 times (p=0.0283), AUC0-t(brain) / AUC0-t(plasma) − by 2.27 times (p=0.0163).
Conclusions. The development of Parkinson’s syndrome, caused by the administration of rotenone, inhibits Pgp functional activity in BBB, which is confirmed by the accumulation in the brain marker substrate of the transporter − fexofenadine.
作者简介
Ivan Chernykh
Ryazan State Medical University
编辑信件的主要联系方式.
Email: ivchernykh88@mail.ru
ORCID iD: 0000-0002-5618-7607
SPIN 代码: 5238-6165
Researcher ID: R-1389-2017
PhD in Biological Sciences, Assistant of the Department of General Chemistry and Pharmachemistry
俄罗斯联邦, RyazanAleksey Shchulkin
Ryazan State Medical University
Email: vestnik@rzgmu.ru
ORCID iD: 0000-0003-1688-0017
SPIN 代码: 2754-1702
Researcher ID: N-9143-2016
MD, PhD, Associate Professor of the Department of Pharmacology with Course of Pharmacy of Faculty Additional Professional Education
俄罗斯联邦, RyazanPavel Mylnikov
Ryazan State Medical University
Email: vestnik@rzgmu.ru
ORCID iD: 0000-0001-7829-2494
SPIN 代码: 8503-3082
Researcher ID: T-8787-2017
PhD-Student of the Department of Pharmacology with Course of Pharmacy of Faculty Additional Professional Education
俄罗斯联邦, RyazanMaria Gatsanoga
Ryazan State Medical University
Email: vestnik@rzgmu.ru
ORCID iD: 0000-0002-1116-6271
SPIN 代码: 9645-5079
Researcher ID: T-3803-2017
MD, PhD, Assistant of the Department of Pharmacology with Course of Pharmacy of Faculty Additional Professional Education
俄罗斯联邦, RyazanMaria Gradinar
Ryazan State Medical University
Email: vestnik@rzgmu.ru
ORCID iD: 0000-0002-2246-4127
Researcher ID: K-3854-2018
student
俄罗斯联邦, RyazanAnna Yesenina
Ryazan State Medical University
Email: vestnik@rzgmu.ru
ORCID iD: 0000-0002-3984-8979
Researcher ID: K-3849-2018
student
俄罗斯联邦, RyazanElena Yakusheva
Ryazan State Medical University
Email: vestnik@rzgmu.ru
ORCID iD: 0000-0001-6887-4888
SPIN 代码: 2865-3080
Researcher ID: T-6343-2017
MD, PhD, Professor, Head of the Department of Pharmacology with Course of Pharmacy of Faculty Additional Professional Education
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