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Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

View Article: PubMed Central - PubMed

ABSTRACT

Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

No MeSH data available.


Transporter expression in brain microvessels. Solute carrier (SLC) superfamily members (green fluorescence) (A) Oatp1a4 and (B) Oct1 and adenosine triphosphate (ATP)–binding cassette (ABC) superfamily representative (C) Mrp2 (red fluorescence) are strongly expressed in brain microvessels directly isolated from rat brain. Scale bar = 4 μm. Figure is an original and represents previously unpublished data.
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f1-10.1177_1179573517693802: Transporter expression in brain microvessels. Solute carrier (SLC) superfamily members (green fluorescence) (A) Oatp1a4 and (B) Oct1 and adenosine triphosphate (ATP)–binding cassette (ABC) superfamily representative (C) Mrp2 (red fluorescence) are strongly expressed in brain microvessels directly isolated from rat brain. Scale bar = 4 μm. Figure is an original and represents previously unpublished data.

Mentions: The BBB is a fundamental component of stroke pathophysiology and an emerging target for treatment opportunities. Physiologically, the BBB is a physical and biochemical barrier that precisely controls CNS uptake of endogenous and exogenous substances including drugs and metabolites. Indeed, brain microvascular endothelial cells form a physical diffusion barrier that prevents free exchange of compounds between blood and brain. Maintenance of BBB properties also requires contribution from other CNS cellular constituents such as pericytes, astrocytes, microglia, and neurons, a concept known as the neurovascular unit (NVU).12 Capillary endothelial cells lack fenestration, display abundant junctional complexes composed of tight and adherens junctions, and have limited pinocytosis. These factors greatly restrict paracellular and transcellular transport of circulating solutes. Indeed, NVU properties render the BBB permeable only to those molecules that are smaller than 400 Da, can form fewer than 8 hydrogen bonds, and are lipophilic in nature.13–15 In fact, it has been suggested that more than 98% of all small molecules cannot permeate the BBB.16 For example, [14C]-histamine, a hydrophilic molecule with molecular size of 111 Da, is detectable in all organs except brain and spinal cord at 5 minutes following intravenous injection in mice.15 In addition to “physical” traits, there are biochemical systems that facilitate drug delivery across the BBB. Such systems include various receptors, such as transferrin, insulin, and low-density liporeceptors (ie, receptor-mediated transcytosis), as well as plasma membrane domains involved in endocytosis of plasma proteins, immunoglobulins, and metalloproteins. Nonspecific transport processes (ie, adsorptive endocytosis) also exist at the BBB and involve electrostatic interactions where cationic proteins bind with anionic binding sites.12,14–17 In contrast, drugs—effectively being solutes with specific kinetic and structural properties—may require putative membrane transporters to get into, and to get out of, brain microvascular endothelial cells. Drug transport mechanisms at the BBB involve numerous proteins of the solute carrier (SLC) and the adenosine triphosphate (ATP)-binding cassette (ABC) superfamilies (Figure 1). Typically, SLC transporters facilitate uptake (ie, influx) of drugs to the CNS, whereas ABC transporters are involved in brain-to-blood (ie, efflux) drug transport.16,18 Several SLC and ABC transporters are functionally expressed on all cellular compartments of the NVU (ie, astrocytes, microglia, pericytes, and neurons). Transport activity in these cell types can lead to significant changes in CNS drug distribution and efficacy, thus creating a secondary barrier to brain drug permeability.12,19–21 Finally, it is important to note that the BBB and blood-cerebrospinal fluid (CSF) barrier localized to the choroid plexus is functionally distinct from the BBB and is involved in maintaining homeostasis of CSF.15,22,23 Although this article will focus on transporters expressed on the BBB, we must acknowledge the “sink” effect that the CSF has by lowering the “steady state” of drugs delivered to the CNS. Such “sink” effects reduce the optimal or targeted concentrations of drugs in the brain that are maintained by the transporter system on BBB and various cells of the CNS.12


Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke
Transporter expression in brain microvessels. Solute carrier (SLC) superfamily members (green fluorescence) (A) Oatp1a4 and (B) Oct1 and adenosine triphosphate (ATP)–binding cassette (ABC) superfamily representative (C) Mrp2 (red fluorescence) are strongly expressed in brain microvessels directly isolated from rat brain. Scale bar = 4 μm. Figure is an original and represents previously unpublished data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5392046&req=5

f1-10.1177_1179573517693802: Transporter expression in brain microvessels. Solute carrier (SLC) superfamily members (green fluorescence) (A) Oatp1a4 and (B) Oct1 and adenosine triphosphate (ATP)–binding cassette (ABC) superfamily representative (C) Mrp2 (red fluorescence) are strongly expressed in brain microvessels directly isolated from rat brain. Scale bar = 4 μm. Figure is an original and represents previously unpublished data.
Mentions: The BBB is a fundamental component of stroke pathophysiology and an emerging target for treatment opportunities. Physiologically, the BBB is a physical and biochemical barrier that precisely controls CNS uptake of endogenous and exogenous substances including drugs and metabolites. Indeed, brain microvascular endothelial cells form a physical diffusion barrier that prevents free exchange of compounds between blood and brain. Maintenance of BBB properties also requires contribution from other CNS cellular constituents such as pericytes, astrocytes, microglia, and neurons, a concept known as the neurovascular unit (NVU).12 Capillary endothelial cells lack fenestration, display abundant junctional complexes composed of tight and adherens junctions, and have limited pinocytosis. These factors greatly restrict paracellular and transcellular transport of circulating solutes. Indeed, NVU properties render the BBB permeable only to those molecules that are smaller than 400 Da, can form fewer than 8 hydrogen bonds, and are lipophilic in nature.13–15 In fact, it has been suggested that more than 98% of all small molecules cannot permeate the BBB.16 For example, [14C]-histamine, a hydrophilic molecule with molecular size of 111 Da, is detectable in all organs except brain and spinal cord at 5 minutes following intravenous injection in mice.15 In addition to “physical” traits, there are biochemical systems that facilitate drug delivery across the BBB. Such systems include various receptors, such as transferrin, insulin, and low-density liporeceptors (ie, receptor-mediated transcytosis), as well as plasma membrane domains involved in endocytosis of plasma proteins, immunoglobulins, and metalloproteins. Nonspecific transport processes (ie, adsorptive endocytosis) also exist at the BBB and involve electrostatic interactions where cationic proteins bind with anionic binding sites.12,14–17 In contrast, drugs—effectively being solutes with specific kinetic and structural properties—may require putative membrane transporters to get into, and to get out of, brain microvascular endothelial cells. Drug transport mechanisms at the BBB involve numerous proteins of the solute carrier (SLC) and the adenosine triphosphate (ATP)-binding cassette (ABC) superfamilies (Figure 1). Typically, SLC transporters facilitate uptake (ie, influx) of drugs to the CNS, whereas ABC transporters are involved in brain-to-blood (ie, efflux) drug transport.16,18 Several SLC and ABC transporters are functionally expressed on all cellular compartments of the NVU (ie, astrocytes, microglia, pericytes, and neurons). Transport activity in these cell types can lead to significant changes in CNS drug distribution and efficacy, thus creating a secondary barrier to brain drug permeability.12,19–21 Finally, it is important to note that the BBB and blood-cerebrospinal fluid (CSF) barrier localized to the choroid plexus is functionally distinct from the BBB and is involved in maintaining homeostasis of CSF.15,22,23 Although this article will focus on transporters expressed on the BBB, we must acknowledge the “sink” effect that the CSF has by lowering the “steady state” of drugs delivered to the CNS. Such “sink” effects reduce the optimal or targeted concentrations of drugs in the brain that are maintained by the transporter system on BBB and various cells of the CNS.12

View Article: PubMed Central - PubMed

ABSTRACT

Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

No MeSH data available.