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The blood-brain barrier: an engineering perspective.

Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC - Front Neuroeng (2013)

Bottom Line: It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain.Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain.Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, Johns Hopkins University Baltimore, MD, USA ; Institute for Nanobiotechnology, Johns Hopkins University Baltimore, MD, USA.

ABSTRACT
It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore, advances in our understanding of the structure and function of the blood-brain barrier are key to developing effective treatments for a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

No MeSH data available.


Related in: MedlinePlus

(A) Permeability of tracers, nutrients, and drugs obtained from in situ rat brain perfusion vs. lipophilicity. (•) Summerfield et al. (2007), (▲) Takasato et al. (1984), (▼) Youdim et al. (2004), (■) Liu et al. (2004) (B) Comparison of permeability of various CNS drugs obtained from transwell assays on monolayers of MDR1-MDCK (P2D) and in situ rat brain perfusions (P3D). P3D values were obtained from in situ rat brain perfusion measurements reported in the literature. For data reported as the permeability surface area products (P3DS, cm3 s−1 gbr−1) we take S = 150 cm2 gbr−1. Values of P3D where S ≠ 150 cm2 gbr−1 were recalculated with S = 150 cm2 gbr−1. Corresponding literature values for logPoct were obtained from calculation Liu et al. (2004), Summerfield et al. (2007), and Youdim et al. (2004) or direct measurement of solute partitioning into octanol and water phases [Takasato et al. (1984)].
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Figure 8: (A) Permeability of tracers, nutrients, and drugs obtained from in situ rat brain perfusion vs. lipophilicity. (•) Summerfield et al. (2007), (▲) Takasato et al. (1984), (▼) Youdim et al. (2004), (■) Liu et al. (2004) (B) Comparison of permeability of various CNS drugs obtained from transwell assays on monolayers of MDR1-MDCK (P2D) and in situ rat brain perfusions (P3D). P3D values were obtained from in situ rat brain perfusion measurements reported in the literature. For data reported as the permeability surface area products (P3DS, cm3 s−1 gbr−1) we take S = 150 cm2 gbr−1. Values of P3D where S ≠ 150 cm2 gbr−1 were recalculated with S = 150 cm2 gbr−1. Corresponding literature values for logPoct were obtained from calculation Liu et al. (2004), Summerfield et al. (2007), and Youdim et al. (2004) or direct measurement of solute partitioning into octanol and water phases [Takasato et al. (1984)].

Mentions: The in vivo 3D permeability for many small molecules increases linearly with lipophilicity up to logPoct ≈ 3, implying that transport from the blood to the brain is dominated by passive transport across the cell membranes (see Figure 8A) (Ohno et al., 1978; Rapoport et al., 1979; Smith and Takasato, 1986; Lipinski et al., 2001; Liu et al., 2004; Summerfield et al., 2007; Zhao et al., 2009). Deviations from this behavior are indicative of other transport mechanisms (Lipinski et al., 2001). For example, D-glucose has a very low lipid solubility (logPoct ≈ −3), but exhibits a high permeability coefficient (P3D ≈ 10−5 cm s−1) since transport is facilitated by the GLUT-1 transporter. Conversely, colchicine has relatively high lipid solubility (logPoct ≈ 2) but has a low permeability coefficient (P3D ≈ 10−6 cm s−1), since it is a substrate of the P-gp efflux pump (Youdim et al., 2003; Liu et al., 2004). Morphine has a relatively low permeability (P3D = 1.1 × 10−6 cm s−1) by drug standards, in part because it is a substrate for the P-gp pump (King et al., 2001), but highlights the fact that relevant doses can be achieved over reasonable time scales (Bouw et al., 2000; Tunblad et al., 2003; Hammarlund-Udenaes et al., 2008). Codeine (methyl morphine) has an -OH group on morphine substituted by a -O-CH3 group, resulting in an increase in logPoct from 0.2 to 1.24, and increased permeability (Bostrom et al., 2008; Hammarlund-Udenaes et al., 2008). Dopamine has an intermediate lipophilicity (logPoct = 0.84) but low permeability (P3D = 1.1 × 10−6 cm s−1). However, L-dopa, a precursor that is metabolized to dopamine in the brain, has a very low lipophilicity (logPoct = −2.53) but high permeability (P3D = 6.6 × 10−6 cm s−1) since it is a substrate for the LAT-1 transporter (Gratton et al., 1997).


The blood-brain barrier: an engineering perspective.

Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC - Front Neuroeng (2013)

(A) Permeability of tracers, nutrients, and drugs obtained from in situ rat brain perfusion vs. lipophilicity. (•) Summerfield et al. (2007), (▲) Takasato et al. (1984), (▼) Youdim et al. (2004), (■) Liu et al. (2004) (B) Comparison of permeability of various CNS drugs obtained from transwell assays on monolayers of MDR1-MDCK (P2D) and in situ rat brain perfusions (P3D). P3D values were obtained from in situ rat brain perfusion measurements reported in the literature. For data reported as the permeability surface area products (P3DS, cm3 s−1 gbr−1) we take S = 150 cm2 gbr−1. Values of P3D where S ≠ 150 cm2 gbr−1 were recalculated with S = 150 cm2 gbr−1. Corresponding literature values for logPoct were obtained from calculation Liu et al. (2004), Summerfield et al. (2007), and Youdim et al. (2004) or direct measurement of solute partitioning into octanol and water phases [Takasato et al. (1984)].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757302&req=5

Figure 8: (A) Permeability of tracers, nutrients, and drugs obtained from in situ rat brain perfusion vs. lipophilicity. (•) Summerfield et al. (2007), (▲) Takasato et al. (1984), (▼) Youdim et al. (2004), (■) Liu et al. (2004) (B) Comparison of permeability of various CNS drugs obtained from transwell assays on monolayers of MDR1-MDCK (P2D) and in situ rat brain perfusions (P3D). P3D values were obtained from in situ rat brain perfusion measurements reported in the literature. For data reported as the permeability surface area products (P3DS, cm3 s−1 gbr−1) we take S = 150 cm2 gbr−1. Values of P3D where S ≠ 150 cm2 gbr−1 were recalculated with S = 150 cm2 gbr−1. Corresponding literature values for logPoct were obtained from calculation Liu et al. (2004), Summerfield et al. (2007), and Youdim et al. (2004) or direct measurement of solute partitioning into octanol and water phases [Takasato et al. (1984)].
Mentions: The in vivo 3D permeability for many small molecules increases linearly with lipophilicity up to logPoct ≈ 3, implying that transport from the blood to the brain is dominated by passive transport across the cell membranes (see Figure 8A) (Ohno et al., 1978; Rapoport et al., 1979; Smith and Takasato, 1986; Lipinski et al., 2001; Liu et al., 2004; Summerfield et al., 2007; Zhao et al., 2009). Deviations from this behavior are indicative of other transport mechanisms (Lipinski et al., 2001). For example, D-glucose has a very low lipid solubility (logPoct ≈ −3), but exhibits a high permeability coefficient (P3D ≈ 10−5 cm s−1) since transport is facilitated by the GLUT-1 transporter. Conversely, colchicine has relatively high lipid solubility (logPoct ≈ 2) but has a low permeability coefficient (P3D ≈ 10−6 cm s−1), since it is a substrate of the P-gp efflux pump (Youdim et al., 2003; Liu et al., 2004). Morphine has a relatively low permeability (P3D = 1.1 × 10−6 cm s−1) by drug standards, in part because it is a substrate for the P-gp pump (King et al., 2001), but highlights the fact that relevant doses can be achieved over reasonable time scales (Bouw et al., 2000; Tunblad et al., 2003; Hammarlund-Udenaes et al., 2008). Codeine (methyl morphine) has an -OH group on morphine substituted by a -O-CH3 group, resulting in an increase in logPoct from 0.2 to 1.24, and increased permeability (Bostrom et al., 2008; Hammarlund-Udenaes et al., 2008). Dopamine has an intermediate lipophilicity (logPoct = 0.84) but low permeability (P3D = 1.1 × 10−6 cm s−1). However, L-dopa, a precursor that is metabolized to dopamine in the brain, has a very low lipophilicity (logPoct = −2.53) but high permeability (P3D = 6.6 × 10−6 cm s−1) since it is a substrate for the LAT-1 transporter (Gratton et al., 1997).

Bottom Line: It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain.Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain.Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, Johns Hopkins University Baltimore, MD, USA ; Institute for Nanobiotechnology, Johns Hopkins University Baltimore, MD, USA.

ABSTRACT
It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore, advances in our understanding of the structure and function of the blood-brain barrier are key to developing effective treatments for a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

No MeSH data available.


Related in: MedlinePlus