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 4^th 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.

Keywords

ABCB1 protein / global cerebral ischemia / lipid peroxidation / Nrf2 / HIF-1α

References

[1] Erokhina PD, Abalenikhina YV, Shchulkin AV, et al. A study of influence of progesterone on activity of Glycoprotein-P in vitro. I. P. Pavlov Russian Medical Biological Herald. 2020;28(2):135–42. (In Russ). doi: 10.23888/PAVLOVJ2020282135-142

[2] Ерохина П.Д., Абаленихина Ю.В., Щулькин А.В., и др. Изучение влияния прогестерона на активность гликопротеина-Р in vitro // Российский медико-биологический вестник имени академика И. П. Павлова. 2020. Т. 28, № 2. С. 135–142. doi: 10.23888/PAVLOVJ2020282135-142

[3] Erokhina PD, Abalenikhina YuV, Shchulkin AV, et al. Study of influence of estradiol on the activity of P-glycoprotein in vitro. Nauka Molodykh (Eruditio Juvenium). 2020;8(3):329–36. (In Russ). doi: 10.23888/HMJ202083329-336

[4] Ерохина П.Д., Абаленихина Ю.В., Щулькин А.В., и др. Изучение влияния эстрадиола на активность гликопротеина-Р in vitro // Наука молодых (Eruditio Juvenium). 2020. Т. 8, № 3. С. 329–336. doi: 10.23888/HMJ202083329-336

[5] Chernykh IV, Shchulkin AV, Pravkin SK, et al. Inhibition of ABCB1 activity in cerebrovascular disease may increase pharmacotherapy effectiveness. Annals of Clinical and Experimental Neurology. 2021;15(1):65–70. (In Russ). doi: 10.25692/ACEN.2021.1.8

[6] Черных И.В., Щулькин А.В., Правкин С.К., и др. Ингибирование активности ABCB1 белка при нарушении мозгового кровообращения может повысить эффективность фармакотерапии // Анналы клинической и экспериментальной неврологии. 2021. Т. 15, № 1. С. 65–70. doi: 10.25692/ACEN.2021.1.8

[7] Duma SN, Ragino YuI. Rol’ antioksidantov v korrektsii psikho-vegetativnykh, astenicheskikh i kognitivnykh narusheniy. Trudnyy Patsiyent. 2011;9(4):28–35. (In Russ).

[8] Дума С.Н., Рагино Ю.И. Роль антиоксидантов в коррекции психовегетативных, астенических и когнитивных нарушений // Трудный пациент. 2011. Т. 9, № 4. С. 28–35.

[9] Yang C, Zhong Z–F, Wang S–P, et al. HIF-1: structure, biology and natural modulators. Chin J Nat Med. 2021;19(7):521–7. doi: 10.1016/S1875-5364(21)60051-1

[10] Yang C., Zhong Z.–F., Wang S.–P., et al. HIF-1: structure, biology and natural modulators // Chin. J. Nat. Med. 2021. Vol. 19, No. 7. P. 521–527. doi: 10.1016/S1875-5364(21)60051-1

[11] Zhang T, Gu J, Wu L, et al. Neuroprotective and axonal out- growth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia. Neuropharmacology. 2017;118:137–47. doi: 10.1016/j.neuropharm.2017.03.022

[12] Zhang T., Gu J., Wu L., et al. Neuroprotective and axonal outgrowth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia // Neuropharmacology. 2017. Vol. 118. P. 137–147. doi: 10.1016/j.neuropharm.2017.03.022

[13] Mazina NV, Volotova EV, Kurkin DV. Neuroprotective action of a new derivative of GABA-RGPU-195 in cerebral ischemia. Fundamental Research. 2013;(6, Pt 6):1473–6. (In Russ).

[14] Мазина Н.В., Волотова Е.В., Куркин Д.В. Нейропротекторное действие нового производного ГАМК-РГПУ-195 при ишемии головного мозга // Фундаментальные исследования. 2013. № 6, Ч. 6. С. 1473–1476.

[15] Cao D, Bai Y, Li L. Common carotid arteries occlusion surgery in adult rats as a model of chronic cerebral hypoperfusion. Bio Protocol. 2018;8(2):e2704. doi: 10.21769/BioProtoc.2704

[16] Cao D., Bai Y., Li L. Common carotid arteries occlusion surgery in adult rats as a model of chronic cerebral hypoperfusion // Bio Protoc. 2018. Vol. 8, No. 2. P. e2704. doi: 10.21769/BioProtoc.2704

[17] Leith CP, Chen IM, Kopecky KJ, et al. Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDRl+/efflux- cases. Blood.1995;86(6):2329–42.

[18] Leith C.P., Chen I.M., Kopecky K.J., et al. Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDRl+/efflux- cases // Blood. 1995. Vol. 86, No. 6. P. 2329–2342.

[19] Ohnishi T, Tamai I, Sakanaka K, et al. In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. Biochem Pharmacol. 1995;49(10):1541–4. doi: 10.1016/0006-2952(95)00082-b

[20] Ohnishi T., Tamai I., Sakanaka K., et al. In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier // Biochem. Pharmacol. 1995. Vol. 49, No. 10. P. 1541–1544. doi: 10.1016/0006-2952(95)00082-b

[21] Sita G, Hrelia P, Tarozzi A, et al. P-glycoprotein (ABCB1) and oxidative stress: focus on Alzheimer’s disease. Oxid Med Cell Longev. 2017;2017:7905486 doi: 10.1155/2017/7905486

[22] Sita G., Hrelia P., Tarozzi A., et al. P-glycoprotein (ABCB1) and oxidative stress: focus on Alzheimer’s disease // Oxid. Med. Cell. Longev. 2017. Vol. 2017. P. 7905486 doi: 10.1155/2017/7905486

[23] Robertson SJ, Kania KD, Hladky SB, Barrand MA. P-glycoprotein expression in immortalised rat brain endothelial cells: comparisons following exogenously applied hydrogen peroxide and after hypoxia–reoxygenation. J Neurochem. 2009;111(1):132–41. doi: 10.1111/j.1471-4159.2009.06306.x

[24] Robertson S.J., Kania K.D., Hladky S.B., et al. P-glycoprotein expression in immortalised rat brain endothelial cells: comparisons following exogenously applied hydrogen peroxide and after hypoxia–reoxygenation // J. Neurochem. 2009. Vol. 111, No. 1. P. 132–141. doi: 10.1111/j.1471-4159.2009.06306.x

[25] Seebacher NA, Richardson DR, Jansson PJ. Glucose modulation induces reactive oxygen species and increases P-glycoprotein-mediated multidrug resistance to chemotherapeutics. Brit J Pharm. 2015;172(10):2557–72. doi: 10.1111/bph.13079

[26] Seebacher N.A., Richardson D.R., Jansson P.J. Glucose modulation induces reactive oxygen species and increases P-glycoprotein-mediated multidrug resistance to chemotherapeutics // Brit. J. Pharm. 2015. Vol. 172, No. 10. P. 2557–2572. doi: 10.1111/bph.13079

[27] Tomita M, Kishimoto H, Takizawa Y, et al. Effects of intestinal ischemia/reperfusion on P-glycoprotein mediated biliary and renal excretion of rhodamine123 in rat. Drug Metab Pharmacokinet. 2009;24(5):428–37. doi: 10.2133/dmpk.24.428

[28] Tomita M., Kishimoto H., Takizawa Y., et al. Effects of intestinal ischemia/reperfusion on P-glycoprotein mediated biliary and renal excretion of rhodamine123 in rat // Drug Metab. Pharmacokinet. 2009. Vol. 24, No. 5. P. 428–437. doi: 10.2133/dmpk.24.428

[29] Shchulkin AV, Abalenikhina YuV, Seidkulieva AA, et al. Effect of Oxidative Stress on the Transport of P-Glycoprotein Substrate through the Cell Monolayer. Biologicheskiye Membrany. 2021;38(4):292–305. (In Russ). doi: 10.31857/S0233475521040101

[30] Щулькин А.В., Абаленихина Ю.В., Сеидкулиева А.А., и др. Влияние окислительного стресса на транспорт субстрата P-гли-копротеина через клеточный монослой // Биологические мембраны. 2021. Т. 38, № 4. С. 292–305. doi: 10.31857/S023347552 1040101

[31] Jeddi F, Soozangar N, Sadeghi MR, et al. Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer. Biomed Pharmacother. 2018;97:286–92. doi: 10.1016/j.biopha.2017.10.129

[32] Jeddi F., Soozangar N., Sadeghi M.R., et al. Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer // Biomed. Pharmacother. 2018. Vol. 97. P. 286–292. doi: 10.1016/j.biopha.2017.10.129

[33] Comerford KM, Wallace TJ, Karhausen J, et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002;62(12):3387–94.

[34] 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. Vol. 62, No. 12. P. 3387–3394.

[35] Trošelj KG, Tomljanović M, Jaganjac M, et al. Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response. Molecules. 2022;27(5):1468. doi: 10.3390/molecules27051468

[36] Trošelj K.G., Tomljanović M., Jaganjac M., et al. Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response // Molecules. 2022. Vol. 27, No. 5. P. 1468. doi: 10.3390/molecules27051468

[37] Parmakhtiar B, Burger RA, Kim J–H, et al. HIF Inactivation of p53 in Ovarian Cancer Can Be Reversed by Topotecan, Restoring Cisplatin and Paclitaxel Sensitivity. Mol Cancer Res. 2019;17(8):1675–86. doi: 10.1158/1541-7786.MCR-18-1109

[38] Parmakhtiar B., Burger R.A., Kim J.–H., et al. HIF Inactivation of p53 in Ovarian Cancer Can Be Reversed by Topotecan, Restoring Cisplatin and Paclitaxel Sensitivity // Mol. Cancer Res. 2019. Vol. 17, No. 8. P. 1675–1686. doi: 10.1158/1541-7786.MCR-18-1109

[39] He J–L, Zhou Z–W, Yin J–J, et al. Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway. Drug Des Develop Ther. 2015;9:127–46. doi: 10.2147/DDDT.S68501

[40] He J.–L., Zhou Z.–W., Yin J.–J., et al. Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway // Drug Des. Devel. Ther. 2014. Vol. 9. P. 127–146. doi: 10.2147/DDDT.S68501

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