Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery

Overview

Journal Handb Exp Pharmacol

Specialty Pharmacology

Date 2021 Mar 6

PMID 33674914

Citations 16

Authors

Robert D Betterton

Thomas P Davis

Patrick T Ronaldson

Affiliations

Soon will be listed here.

Abstract

Therapeutic delivery to the central nervous system (CNS) continues to be a considerable challenge in the pharmacological treatment and management of neurological disorders. This is primarily due to the physiological and biochemical characteristics of brain barrier sites (i.e., blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB)). Drug uptake into brain tissue is highly restricted by expression of tight junction protein complexes and adherens junctions between brain microvascular endothelial cells and choroid plexus epithelial cells. Additionally, efflux transport proteins expressed at the plasma membrane of these same endothelial and epithelial cells act to limit CNS concentrations of centrally acting drugs. In contrast, facilitated diffusion via transporter proteins allows for substrate-specific flux of molecules across the plasma membrane, directing drug uptake into the CNS. Organic Cation Transporters (OCTs) and Novel Organic Cation Transporters (OCTNs) are two subfamilies of the solute carrier 22 (SLC22) family of proteins that have significant potential to mediate delivery of positively charged, zwitterionic, and uncharged therapeutics. While expression of these transporters has been well characterized in peripheral tissues, the functional expression of OCT and OCTN transporters at CNS barrier sites and their role in delivery of therapeutic drugs to molecular targets in the brain require more detailed analysis. In this chapter, we will review current knowledge on localization, function, and regulation of OCT and OCTN isoforms at the BBB and BCSFB with a particular emphasis on how these transporters can be utilized for CNS delivery of therapeutic agents.

Citing Articles

Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease.

Roberts C, Raabe N, Wiegand L, Kadar Shahib A, Rastegar M Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770443 PMC: 11677501. DOI: 10.3390/ph17121601.

Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration.

Pingitore V, Pancholi J, Hornsby T, Warne J, Pryce G, McCormick L Sci Adv. 2024; 10(28):eado3501.

PMID: 38985859 PMC: 11235165. DOI: 10.1126/sciadv.ado3501.

Circadian ABCG2 Expression Influences the Brain Uptake of Donepezil across the Blood-Cerebrospinal Fluid Barrier.

Furtado A, Duarte A, Costa A, Goncalves I, Santos C, Gallardo E Int J Mol Sci. 2024; 25(9).

PMID: 38732233 PMC: 11084460. DOI: 10.3390/ijms25095014.

Metabolite transport across central nervous system barriers.

Carstens G, Verbeek M, Rohlwink U, Figaji A, Te Brake L, van Laarhoven A J Cereb Blood Flow Metab. 2024; 44(7):1063-1077.

PMID: 38546534 PMC: 11179608. DOI: 10.1177/0271678X241241908.

A case report of treatment of a streptococcal brain abscess with ceftobiprole supported by the measurement of drug levels in the cerebrospinal fluid.

Giuliano S, Angelini J, Flammini S, Della Siega P, Vania E, Montanari L Heliyon. 2024; 10(6):e27285.

PMID: 38515704 PMC: 10955256. DOI: 10.1016/j.heliyon.2024.e27285.

References

Urakami Y, Okuda M, Saito H, Inui K . Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett. 2000; 473(2):173-6. DOI: 10.1016/s0014-5793(00)01525-8. View

Li L, Sun L, Qiu Y, Zhu W, Hu K, Mao J . Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway. Front Pharmacol. 2020; 11:64. PMC: 7041339. DOI: 10.3389/fphar.2020.00064. View

Ishimoto T, Nakamichi N, Nishijima H, Masuo Y, Kato Y . Carnitine/Organic Cation Transporter OCTN1 Negatively Regulates Activation in Murine Cultured Microglial Cells. Neurochem Res. 2017; 43(1):116-128. DOI: 10.1007/s11064-017-2350-5. View

Sekhar G, Fleckney A, Boyanova S, Rupawala H, Lo R, Wang H . Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer's disease. Fluids Barriers CNS. 2019; 16(1):38. PMC: 6915870. DOI: 10.1186/s12987-019-0158-1. View

Garcia-Bea A, Miranda-Azpiazu P, Muguruza C, Marmolejo-Martinez-Artesero S, Diez-Alarcia R, Gabilondo A . Serotonin 5-HT receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via G-proteins. Eur Neuropsychopharmacol. 2019; 29(12):1453-1463. DOI: 10.1016/j.euroneuro.2019.10.013. View

Jiang W, Prokopenko O, Wong L, Inouye M, Mirochnitchenko O . IRIP, a new ischemia/reperfusion-inducible protein that participates in the regulation of transporter activity. Mol Cell Biol. 2005; 25(15):6496-508. PMC: 1190334. DOI: 10.1128/MCB.25.15.6496-6508.2005. View

Ahn A, Basbaum A . Where do triptans act in the treatment of migraine?. Pain. 2005; 115(1-2):1-4. PMC: 1850935. DOI: 10.1016/j.pain.2005.03.008. View

Inano A, Sai Y, Nikaido H, Hasimoto N, Asano M, Tsuji A . Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2. Biopharm Drug Dispos. 2003; 24(8):357-65. DOI: 10.1002/bdd.371. View

Ciarimboli G, Struwe K, Arndt P, Gorboulev V, Koepsell H, Schlatter E . Regulation of the human organic cation transporter hOCT1. J Cell Physiol. 2004; 201(3):420-8. DOI: 10.1002/jcp.20081. View

10.

Morris M, Rodriguez-Cruz V, Felmlee M . SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers. AAPS J. 2017; 19(5):1317-1331. PMC: 6467070. DOI: 10.1208/s12248-017-0110-8. View

11.

Stopa E, Tanis K, Miller M, Nikonova E, Podtelezhnikov A, Finney E . Comparative transcriptomics of choroid plexus in Alzheimer's disease, frontotemporal dementia and Huntington's disease: implications for CSF homeostasis. Fluids Barriers CNS. 2018; 15(1):18. PMC: 5977762. DOI: 10.1186/s12987-018-0102-9. View

12.

Wu X, Prasad P, Leibach F, Ganapathy V . cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun. 1998; 246(3):589-95. DOI: 10.1006/bbrc.1998.8669. View

13.

Li Q, Yang H, Peng X, Guo D, Dong Z, Polli J . Ischemia/Reperfusion-inducible protein modulates the function of organic cation transporter 1 and multidrug and toxin extrusion 1. Mol Pharm. 2013; 10(7):2578-87. PMC: 3773277. DOI: 10.1021/mp400013t. View

14.

Gorelick P . The global burden of stroke: persistent and disabling. Lancet Neurol. 2019; 18(5):417-418. DOI: 10.1016/S1474-4422(19)30030-4. View

15.

Sekhar G, Georgian A, Sanderson L, Vizcay-Barrena G, Brown R, Muresan P . Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB). PLoS One. 2017; 12(3):e0173474. PMC: 5376088. DOI: 10.1371/journal.pone.0173474. View

16.

Witt K, Mark K, Sandoval K, Davis T . Reoxygenation stress on blood-brain barrier paracellular permeability and edema in the rat. Microvasc Res. 2007; 75(1):91-6. PMC: 2243179. DOI: 10.1016/j.mvr.2007.06.004. View

17.

Grundemann D, Koster S, Kiefer N, Breidert T, Engelhardt M, Spitzenberger F . Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J Biol Chem. 1998; 273(47):30915-20. DOI: 10.1074/jbc.273.47.30915. View

18.

Vialou V, Amphoux A, Zwart R, Giros B, Gautron S . Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J Neurosci. 2004; 24(11):2846-51. PMC: 6729503. DOI: 10.1523/JNEUROSCI.5147-03.2004. View

19.

Liddelow S . Development of the choroid plexus and blood-CSF barrier. Front Neurosci. 2015; 9:32. PMC: 4347429. DOI: 10.3389/fnins.2015.00032. View

20.

Lau H, Ng N, Loo L, Jasmen J, Teo A . The molecular functions of hepatocyte nuclear factors - In and beyond the liver. J Hepatol. 2017; 68(5):1033-1048. DOI: 10.1016/j.jhep.2017.11.026. View