TY - CHAP
T1 - Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites
T2 - Focus on CNS Drug Delivery
AU - Betterton, Robert D.
AU - Davis, Thomas P.
AU - Ronaldson, Patrick T.
N1 - Funding Information:
This work is funded by grants from the National Institutes of Neurological Diseases and Stroke (NINDS; R01 NS084941) and the American Heart Association (19TPA34910113) to PTR and by a grant from the National Institute on Drug Abuse (NIDA; R01 DA051812) to TPD and PTR.
Publisher Copyright:
© 2021, The Author(s), under exclusive license to Springer Nature Switzerland AG.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Blood–Brain Barrier (BBB)
KW - Blood–Cerebrospinal Fluid Barrier (BCSFB)
KW - Brain parenchymal transporters
KW - CNS drug delivery
KW - Organic cation transport
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U2 - 10.1007/164_2021_448
DO - 10.1007/164_2021_448
M3 - Chapter
C2 - 33674914
AN - SCOPUS:85118472901
T3 - Handbook of Experimental Pharmacology
SP - 301
EP - 328
BT - Handbook of Experimental Pharmacology
PB - Springer Science and Business Media Deutschland GmbH
ER -