Drug Transport in the Brain

Sangha, Vishal; Williams, Erica I.; Ronaldson, Patrick T.; Bendayan, Reina

doi:10.1002/9781119739883.ch14

Cited by 5 publications

(9 citation statements)

References 349 publications

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“…Endogenous BBB transporters include members of the ABC (ATP-binding cassette) superfamily and SLC (solute carrier) family. 107 Working in consort, transporters provide biochemical barrier properties to the BBB, controlling entry for some substances while restricting the permeability of others. Transporter isoforms at the BBB function similarly to well-characterized systems localized in other tissues, although distribution and rates of transport can vary.…”

Section: Transporters: the Next Frontier For Drug Delivery In Strokementioning

confidence: 99%

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside

Ronaldson,

Williams,

Betterton

et al. 2024

Stroke

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Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.

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Section: Transporters: the Next Frontier For Drug Delivery In Strokementioning

confidence: 99%

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside

Ronaldson,

Williams,

Betterton

et al. 2024

Stroke

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“…In addition to a physical barrier that is provided by the BBB, the endothelial cells of the brain possess an enzymatic activity that permits some compounds to be degraded before their passage over the BBB (Lorke et al, 2008;Upadhyay, 2014). Brain endothelial cells are known to express a number of important transport proteins, including organic anion carriers (OATs), P-glycoprotein/MDR1 (Pgp), multidrug resistance-associated protein 1 (MRPs), breast cancer-resistant protein (BCRP), and several other proteins (Englund, 2005;Löscher and Potschka, 2005;Sangha et al, 2022). These proteins control the pathway of several different xenobiotics and drugs.…”

Section: Challenges Of Regular Drug Delivery To the Cnsmentioning

confidence: 99%

Exploring the role of nanomedicines for the therapeutic approach of central nervous system dysfunction: At a glance

Rhaman

Islam

Akash

et al. 2022

Front. Cell Dev. Biol.

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In recent decades, research scientists, molecular biologists, and pharmacologists have placed a strong emphasis on cutting-edge nanostructured materials technologies to increase medicine delivery to the central nervous system (CNS). The application of nanoscience for the treatment of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), brain cancer, and hemorrhage has the potential to transform care. Multiple studies have indicated that nanomaterials can be used to successfully treat CNS disorders in the case of neurodegeneration. Nanomedicine development for the cure of degenerative and inflammatory diseases of the nervous system is critical. Nanoparticles may act as a drug transporter that can precisely target sick brain sub-regions, boosting therapy success. It is important to develop strategies that can penetrate the blood–brain barrier (BBB) and improve the effectiveness of medications. One of the probable tactics is the use of different nanoscale materials. These nano-based pharmaceuticals offer low toxicity, tailored delivery, high stability, and drug loading capacity. They may also increase therapeutic effectiveness. A few examples of the many different kinds and forms of nanomaterials that have been widely employed to treat neurological diseases include quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These unique qualities, including sensitivity, selectivity, and ability to traverse the BBB when employed in nano-sized particles, make these nanoparticles useful for imaging studies and treatment of NDs. Multifunctional nanoparticles carrying pharmacological medications serve two purposes: they improve medication distribution while also enabling cell dynamics imaging and pharmacokinetic study. However, because of the potential for wide-ranging clinical implications, safety concerns persist, limiting any potential for translation. The evidence for using nanotechnology to create drug delivery systems that could pass across the BBB and deliver therapeutic chemicals to CNS was examined in this study.

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“…There are complex transport processes within unique barriers in the central nervous system (CNS) that regulate the availability of a variety of micronutrients required for neural development and function. These include the blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB) at the choroid plexus (CP), and the less studied arachnoid barrier (AB) (or blood–arachnoid barrier) [ 1 , 36 ]. These barriers limit paracellular transport of molecules into the CNS at tight junctions populated with claudins, occludins (and others) , and at endothelial/epithelial and ependymal cell interfaces.…”

Section: Introductionmentioning

confidence: 99%

“…These barriers limit paracellular transport of molecules into the CNS at tight junctions populated with claudins, occludins (and others) , and at endothelial/epithelial and ependymal cell interfaces. There are a variety of transporters belonging to the ATP-binding cassette (ABC), solute carrier (SLC) superfamilies and channels expressed at these sites providing highly specialized control of nutrients, metabolites and fluid that enter and exit the CNS [ 1 , 11 , 25 , 36 ]. Transporters within cells of the brain parenchyma (i.e., astrocytes, microglia, neurons) provide further highly specific mechanisms by which substances are delivered to neural tissues [ 7 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…There are a variety of transporters belonging to the ATP-binding cassette (ABC), solute carrier (SLC) superfamilies and channels expressed at these sites providing highly specialized control of nutrients, metabolites and fluid that enter and exit the CNS [ 1 , 11 , 25 , 36 ]. Transporters within cells of the brain parenchyma (i.e., astrocytes, microglia, neurons) provide further highly specific mechanisms by which substances are delivered to neural tissues [ 7 , 36 ]. Together, these cells within physical and biochemical barriers work in concert to regulate CNS homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Novel localization of folate transport systems in the murine central nervous system

Sangha

Hoque

Henderson

et al. 2022

Fluids Barriers CNS

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Background Folates are a family of B9 vitamins that serve as one-carbon donors critical to biosynthetic processes required for the development and function of the central nervous system (CNS) in mammals. Folate transport is mediated by three highly specific systems: (1) folate receptor alpha (FRα; FOLR1/Folr1), (2) the reduced folate-carrier (RFC; SLC19A1/Slc19a1) and (3) the proton-coupled folate transporter (PCFT; SLC46A1/Slc46a1). Folate transport into and out of the CNS occurs at the blood–cerebrospinal fluid barrier (BCSFB), mediated by FRα and PCFT. Impairment of folate transport at the BCSFB results in cerebral folate deficiency in infants characterized by severe neurological deficiencies and seizures. In contrast to the BCSFB, CNS folate transport at other brain barriers and brain parenchymal cells has not been extensively investigated. The aim of this study is to characterize folate transport systems in the murine CNS at several known barriers encompassing the BCSFB, arachnoid barrier (AB), blood–brain barrier (BBB) and parenchymal cells (astrocytes, microglia, neurons). Methods Applying immunohistochemistry, localization of folate transport systems (RFC, PCFT, FRα) was examined at CNS barriers and parenchymal sites in wildtype (C57BL6/N) mice. Subcellular localization of the folate transport systems was further assessed in an in vitro model of the mouse AB. Gene and protein expression was analyzed in several in vitro models of brain barriers and parenchyma by qPCR and western blot analysis. Results RFC, PCFT, and FRα expression was localized within the BCSFB and BBB consistent with previous reports. Only RFC and PCFT expression was detected at the AB. Varied levels of RFC and PCFT expression were detected in neuronal and glial cells. Conclusions Localization of RFC and PCFT within the AB, described here for the first time, suggest that AB may contribute to folate transport between the peripheral circulation and the CSF. RFC and PCFT expression observed in astrocytes and microglia is consistent with the role that one or both of these transporters may play in delivering folates into cells within brain parenchyma. These studies provide insights into mechanisms of folate transport in the CNS and may enhance our understanding of the critical role folates play in neurodevelopment and in the development of novel treatment strategies for disorders of brain folate deficiency due to impaired transporter function.

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Drug Transport in the Brain

Cited by 5 publications

References 349 publications

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside

Exploring the role of nanomedicines for the therapeutic approach of central nervous system dysfunction: At a glance

Novel localization of folate transport systems in the murine central nervous system

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