Volume 9 Supplement 1
Characteristics of compounds that cross the blood-brain barrier
© Banks; licensee BioMed Central Ltd. 2009
Published: 12 June 2009
Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.
The BBB serves roles other than that of blocking circulating substances from entering the CNS. It also facilitates and regulates the entry of many substances that are critical to CNS function and secretes substances into the blood and CNS. These extra-barrier functions allow the BBB to influence the homeostatic, nutritive, and immune environments of the CNS and to regulate the exchange of informational molecules between the CNS and blood . An understanding of the barrier and extra-barrier aspects of BBB physiology is critical to developing drugs that can access the CNS .
General characteristics of the blood-brain barrier
Three major modifications to the capillary bed of the brain prevent the formation of a plasma ultrafiltrate in the CNS (Figure 1): tight junctions that cement together brain endothelial cells that are in apposition, a greatly reduced rate of pinocytosis, and a lack of intracellular fenestrations . These modifications prevent the unregulated leakage of serum proteins into the CNS under normal conditions. Substances are still able to cross the vascular BBB by a variety of mechanisms. These mechanisms include transmembrane diffusion, saturable transport, adsorptive endocytosis, and the extracellular pathways. Below, we discuss transmembrane diffusion and saturable transporters. Reviews on adsorptive endocytosis and the extracellular pathways can be found elsewhere [7, 8].
Most drugs cross the BBB by transmembrane diffusion . This is a non-saturable mechanism that depends on the drug melding into the cell membrane. A low molecular weight and high degree of lipid solubility favor crossing by this mechanism. However, a drug taken up by the membranes that form the BBB must then partition into the aqueous environment of the brain's interstitial fluid to exert an effect. As a result, a substance that is too lipid soluble can be sequestered by the capillary bed and not reach the cells behind the BBB. Lipid solubility also favors uptake by the peripheral tissues; this, in turn, lowers the concentration of the drug in blood. Thus, while lipid solubility can increase transport rate across the BBB, it can also lower the amount of the drug presented to the BBB. The percent of administered drug entering the brain is determined by both the rate of transport across the BBB and the amount of drug presented to the brain . Use of lipid solubility to improve drug delivery to the brain must thus find the balance between increased permeation of the BBB and decreased concentrations in blood.
Factors in addition to lipid solubility affect the ability of a drug to partition from blood into the BBB. These include charge, tertiary structure and degree of protein binding. Chief among these secondary factors, however, is molecular weight. The best approximation of the influence of size on BBB penetration is that it is inversely related to the square route of molecular weight. Reviews often quote an absolute cut-off of 400 to 600 Da for penetration of the BBB, but these arise from a misreading of the literature. The 'Rule of 5' of Lipinski found that from a library of drugs selected for gastrointestinal absorption, few substances were over 500 Da . Some reviewers have uncritically applied the Rule of 5, including this one, to the BBB. A study of 27 substances by Levin  found that the four drugs in this groups with molecular weights over 400 Da had no measurable brain uptake. However, it is now known that these substances are all substrates for P-glycoprotein, a major brain-to-blood, or efflux, pump located at the BBB that prevents or greatly retards a large number of small, lipid soluble molecules from entering the CNS [12, 13]. Peptides and proteins with molecular weights in excess of 600 Da are known to cross the BBB in amounts sufficient to affect CNS function. Early examples include delta sleep-inducing peptide and enkephalin analogs. The largest substance found to date to cross the BBB by the mechanism of transmembrane diffusion is cytokine-induced neutrophil chemoattractant-1 (CINC-1) at 7,800 Da .
Lipophilic substances of low molecular weight tend to be substrates for P-glycoprotein . Brain-to-blood efflux by P-glycoprotein can greatly limit the rate of uptake by the BBB and is a major obstacle in drug development. The pharmacogenomics of P-glycoprotein show that about 30% of the population overexpress it and so are less sensitive to the CNS effects of its ligands, while about 25% of the population underexpress it . Such individual variation has been linked to sensitivity to drugs for the treatment of AIDS and epilepsy [15, 16].
Saturable transport systems
Some drugs or substances used for drug-like effects cross the BBB by use of saturable transport systems. L-DOPA and caffeine are examples as are vitamins such as B12 and B6 . The uptake rate across the BBB for an endogenous ligand of a transporter is roughly about 10 times higher than would be expected if it crossed by transmembrane diffusion . Additionally, many of the transporters for regulatory molecules, such as peptides and regulatory proteins, are taken up selectively by specific brain regions [19, 20]. Thus, exploitation of transporters offer the drug development field not only high uptake rates for large, water soluble compounds but targeting to specific regions of the CNS.
Efflux transporters have the opposite effect to influx transporters in that they decrease the uptake rate of potential drugs . P-glycoprotein has been discussed above, but the BBB possesses many other efflux transporters. As discussed below, peptide transport system-6 (PTS-6) retards the accumulation from blood by brain of the 27 amino acid form of pituitary adenylate cyclase activating polypeptide (PACAP27) .
The rate at which saturable systems transport their ligands across the BBB is often regulated. For flow-dependent substances such as glucose, transport rate is a function of cerebral blood flow . For substances that are more slowly transported, a variety of agents have been found to alter transport. For example, leucine regulates the transport rate of peptide transport system-1 (PTS-1)  and epinephrine and triglycerides affect leptin, ghrelin, and insulin transport [23–25].
Under physiological conditions, the BBB transporters adapt to serve the needs of the CNS. Uncoupling between BBB functions and CNS needs is accompanied by disease states . For example, decreased leptin transport is associated with peripheral leptin resistance in obesity  and decreased efflux of amyloid beta protein is associated with Alzheimer's disease .
General strategies for drug transport
A great deal of current effort towards drug development is directed towards in silico analysis and high-throughput screening. Such efforts limit drug discovery to substances crossing the BBB by transmembrane diffusion. They also limit discovery to the main parameters in the library used as the basis of computation. In silico methods are likely less efficient in the search for CNS drug candidates than in the search for those absorbed by the gastrointestinal tract because of a number of parameters that can modify or override transmembrane diffusion: cerebral blood flow, influx and efflux transporters, protein binding in the blood, clearance from blood, sequestration by BBB tissues, and enzymatic activity by peripheral tissues, blood, the CNS and at the BBB .
Many approaches to drug development have attempted to harness transporters. The usual approach is a version of the 'Trojan horse' strategy . Here, a substance that does not cross the BBB is coupled to a substance that does. Such coupling can have the added benefit of improving peripheral pharmacokinetics. Unfortunately, the resulting hybrid compound is often not recognized by the original transporter or the transporter/hybrid compound is routed to lysosomes for destruction. Hybrids coupled to other substances may use other vesicular pathways across the BBB. Unfortunately, the cell biology of BBB vesicular systems is poorly understood and this impairs exploitation of promising leads.
Development of analogs of transported ligands has been slow. Many endogenous substances that could be the basis of CNS drugs, such as the feeding hormones and cytokines, are transported across the BBB . However, the endogenous compounds have poor peripheral pharmacokinetics and this limits their usefulness . Analogs would have to retain their affinity for both the BBB transporter and for the CNS receptor while becoming less favorable for peripheral enzymes and clearance mechanisms.
When disease states affect the BBB or the BBB is itself impaired, then it becomes a therapeutic target in its own right . A classic example is multiple sclerosis in which the BBB becomes leaky and allows the entry of immune cells into the CNS. However, the passage of immune cells across the BBB is a highly regulated process  and the leakage is likely a byproduct of immune cell trafficking and not the other way round . Obviously, the luminal surface of the capillary bed does not require passage across the BBB and, hence, drug strategies used to target peripheral tissues are applicable to this half of the BBB. Luminal receptors that induce brain endothelial cells to secrete into the CNS substances such as prostaglandins, cytokines, and nitric oxide are also readily targetable. This suggests that the BBB itself could be used as the source of CNS 'drugs'.
'Bypassing' the BBB can also be an effective strategy, especially for selected cases or situations. For example, intrathecal administration for delivery of drug to the brain is ineffectual for small, lipid soluble drugs . However, this route may be an option for large regulatory proteins with negligible brain-to-blood efflux . Intranasal delivery of drugs, including peptides , shows a great deal of promise . Nasal delivery of insulin, for example, has had positive effects in treating Alzheimer's disease [37, 38].
Examples and special cases
The various strategies used to develop drugs towards the CNS are meeting with varied levels of success. Those that consider the special features of the BBB rather than 'black boxing' it, attempt to understand the underlying mechanisms of promising leads, and consider the peripheral pharmacokinetics of the candidate drug should have advantages. However, there is a great deal that is unknown about the BBB that would be of great use to CNS drug development. For example, there are likely a great many BBB transporters yet to be discovered. Below, we consider two newly discovered transporters and their early applications to drug development.
Antisense molecules have been assumed to be incapable of crossing the BBB. The rapid clearance of any mRNA material in the circulation would certainly justify this assumption. However, enzymatically resistant analogs such as peptide nucleic acids and phosphorothioate oligonucleotides (PONs) can cross the BBB in sufficient amounts to affect CNS function [39, 40]. The PONs are transported across the BBB by a saturable transport system. This transporter has been used to deliver an antisense molecule directed against amyloid precursor protein, which effectively reverses the cognitive deficit in an animal model of Alzheimer's disease. PONs have also been directed at the efflux transporter of PACAP27 . The PONs reduce expression of the transporter, increase PACAP27 retention by brain after its peripheral administration, and improve outcomes in animal models of stroke and Alzheimer's disease. These results show that targeting efflux systems at the BBB with antisense molecules can improve drug delivery to the brain.
Mucopolysaccharidoses consist of a number of diseases in which missing enzymes lead to the accumulation of glycosaminoglycans in brain and peripheral tissues. Enzyme replacement clears the glycosaminoglycans from the peripheral tissues, but not from the CNS as the enzymes do not cross the BBB. However, it was recently discovered that the mannose-6 phosphate receptor acts as a saturable transporter at the neonatal BBB [42, 43]. As a result, enzyme given to the neonate is effective in clearance of glycosaminoglycans from the CNS [44–46]. Unfortunately, this transport function is lost with development. Recent work has shown that transporter function can be re-induced in the adult with epinephrine . How epinephrine invokes this re-induction of activity is unclear, but it may be a useful strategy for delivery of enzyme to the CNS.
The BBB is a complex regulatory interface that possesses barrier, secretory, enzymatic, and transporter activities. Transmembrane diffusion, harnessing of transporters, adsorptive endocytosis, and extracellular pathways are some of the mechanisms being exploited for drug delivery. Unfortunately, our understanding of the BBB in many areas, especially those of saturable transport systems and vesicular pathways, is limited. Future successes in CNS drug discovery will likely result from an interplay of exploratory research and rational drug development.
List of abbreviations used
central nervous system
pituitary adenylate cyclase activating polypeptide
This article has been published as part of BMC Neurology Volume 9 Supplement 1, 2009: Proceedings of the 2009 Drug Discovery for Neurodegeneration Conference. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2377/9?issue=S1.
- Neuwelt E, Abbott NJ, Abrey L, Banks WA, Blakley B, Davis T, Engelhardt B, Grammas P, Nedergaard M, Nutt J, Pardridge W, Rosenberg GA, Smith Q, Drewes LR: Strategies to advance translational research into brain barriers. Lancet Neurol. 2008, 7: 84-96. 10.1016/S1474-4422(07)70326-5.View ArticlePubMedGoogle Scholar
- Johanson CE, Duncan JA, Stopa EG, Baird A: Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharm Res. 2005, 22: 1011-1037. 10.1007/s11095-005-6039-0.View ArticlePubMedGoogle Scholar
- Begley DJ: Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther. 2007, 104: 29-45. 10.1016/j.pharmthera.2004.08.001.View ArticleGoogle Scholar
- Quan N, Banks WA: Brain-immune communication pathways. Brain Behav Immun. 2007, 21: 727-735. 10.1016/j.bbi.2007.05.005.View ArticlePubMedGoogle Scholar
- Greig NH, Brossi A, Pei XF, Ingram DK, Soncrant TT: Designing drugs for optimal nervous system activity. New Concepts of a Blood-brain Barrier. Edited by: Greenwood J, Begley DJ, Segal MB. 1995, New York: Plenum Press, 251-264.View ArticleGoogle Scholar
- Reese TS, Karnovsky MJ: Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol. 1967, 34: 207-217. 10.1083/jcb.34.1.207.PubMed CentralView ArticlePubMedGoogle Scholar
- Banks WA: Are the extracellular pathways a conduit for the delivery of therapeutics to the brain?. Curr Pharm Des. 2004, 10: 1365-1370. 10.2174/1381612043384862.View ArticlePubMedGoogle Scholar
- Broadwell RD: Transcytosis of macromolecules through the blood-brain barrier: a cell biological perspective and critical appraisal. Acta Neuropathol. 1989, 79: 117-128. 10.1007/BF00294368.View ArticlePubMedGoogle Scholar
- Oldendorf WH: Lipid solubility and drug penetration of the blood-brain barrier. Proc Soc Exp Biol Med. 1974, 147: 813-816.View ArticlePubMedGoogle Scholar
- Lipinski CA, Lombardo F, Dominy BW, Feeney PJ: Experimental and computational approaches to estimate solubility and permeability in drug discovery and developmental settings. Adv Drug Deliv Rev. 1997, 23: 3-25. 10.1016/S0169-409X(96)00423-1.View ArticleGoogle Scholar
- Levin VA: Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem. 1980, 23: 682-684. 10.1021/jm00180a022.View ArticlePubMedGoogle Scholar
- Begley DJ: ABC transporters and the blood-brain barrier. Curr Pharm Des. 2004, 10: 1295-1312. 10.2174/1381612043384844.View ArticlePubMedGoogle Scholar
- Taylor EM: The impact of efflux transporters in the brain on the development of drugs for CNS disorders. Clin Pharmacokinet. 2002, 41: 81-92. 10.2165/00003088-200241020-00001.View ArticlePubMedGoogle Scholar
- Pan W, Kastin AJ: Changing the chemokine gradient: CINC1 crosses the blood-brain barrier. J Neuroimmunol. 2001, 115: 64-70. 10.1016/S0165-5728(01)00256-9.View ArticlePubMedGoogle Scholar
- Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, Decosterd LA, Furrer H, Opravil M, Pantaleo G, Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, Telenti A, Swiss HIV Cohort Study: Response to antiretrovial treatment in HIV-1 infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetic study. Lancet. 2002, 359: 30-36. 10.1016/S0140-6736(02)07276-8.View ArticlePubMedGoogle Scholar
- Löscher W, Potschka H: Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther. 2002, 30: 7-14. 10.1124/jpet.301.1.7.View ArticleGoogle Scholar
- Davson H, Welch K, Segal MB: Some special aspects of the blood-brain barrier. The Physiology and Pathophysiology of the Cerebrospinal Fluid. 1987, Edinburgh: Churchill Livingstone, 247-374.Google Scholar
- Oldendorf WH: Brain uptake of radio-labelled amino acids, amines and hexoses after arterial injection. Am J Physiol. 1971, 221: 1629-1639.PubMedGoogle Scholar
- Banks WA, Kastin AJ: Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides. 1998, 19: 883-889. 10.1016/S0196-9781(98)00018-7.View ArticlePubMedGoogle Scholar
- Banks WA, Moinuddin A, Morley JE: Regional transport of TNF-α across the blood-brain barrier in young ICR and young and aged SAMP8 mice. Neurobiol Aging. 2001, 22: 671-676. 10.1016/S0197-4580(01)00220-2.View ArticlePubMedGoogle Scholar
- Banks WA, Kastin AJ, Komaki G, Arimura A: Passage of pituitary adenylate cyclase activating polypeptide1–27 and pituitary adenylate cyclase activating polypeptide1–38 across the blood-brain barrier. J Pharmacol Exp Ther. 1993, 267: 690-696.PubMedGoogle Scholar
- Banks WA, Kastin AJ: Modulation of the carrier-mediated transport of the Tyr-MIF-1 across the blood-brain barrier by essential amino acids. J Pharmacol Exp Ther. 1986, 239: 668-672.PubMedGoogle Scholar
- Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, Morley JE: Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes. 2004, 53: 1253-1260. 10.2337/diabetes.53.5.1253.View ArticlePubMedGoogle Scholar
- Banks WA, Burney BO, Robinson SM: Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier. Peptides. 2008, 29: 2061-2065. 10.1016/j.peptides.2008.07.001.PubMed CentralView ArticlePubMedGoogle Scholar
- Urayama A, Banks WA: Starvation and triglycerides reverse the obesity-induced impairment of insulin transport at the blood-brain barrier. Endocrinology. 2008, 149: 3592-3597. 10.1210/en.2008-0008.PubMed CentralView ArticlePubMedGoogle Scholar
- Banks WA: Editorial: The blood-brain barrier as a cause of disease. Curr Pharm Des. 2008, 14: 1553-1554. 10.2174/138161208784705478.View ArticlePubMedGoogle Scholar
- Banks WA: The blood-brain barrier as a cause of obesity. Curr Pharm Des. 2008, 14: 1606-1614. 10.2174/138161208784705496.View ArticlePubMedGoogle Scholar
- Deane R, Sagare A, Zlokovic B: The role of the cell surface LRP and soluble LRP in blood-brain barrier Aβ clearance in Alzheimer's disease. Curr Pharm Des. 2008, 14: 1601-1605. 10.2174/138161208784705487.PubMed CentralView ArticlePubMedGoogle Scholar
- Penichet ML, Kang YS, Pardridge WM, Morrison SL, Shin SU: An antibody-avidin fusion protein specific for the transferrin receptor serves as a delivery vehicle for effective brain targeting: initial applications in anti-HIV antisense drug delivery to the brain. J Immunol. 1999, 163: 4421-4426.PubMedGoogle Scholar
- Pan W, Kastin AJ: Cytokine transport across the injured blood-spinal cord barrier. Curr Pharm Des. 2008, 14: 1620-1624. 10.2174/138161208784705450.PubMed CentralView ArticlePubMedGoogle Scholar
- Engelhardt B: The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Curr Pharm Des. 2008, 14: 1555-1565. 10.2174/138161208784705432.View ArticlePubMedGoogle Scholar
- Toborek M, Lee YW, Flora G, Pu H, András IE, Wylegala E, Hennig B, Nath A: Mechanisms of the blood-brain barrier disruption in HIV-1 infection. Cell Mol Neurobiol. 2005, 25: 181-199. 10.1007/s10571-004-1383-x.View ArticlePubMedGoogle Scholar
- McQuay HJ, Sullivan AF, Smallman K, Dickenson AH: Intrathecal opioids, potency and lipophilicity. Pain. 1989, 36: 111-115. 10.1016/0304-3959(89)90118-8.View ArticlePubMedGoogle Scholar
- McCarthy TJ, Banks WA, Farrell CL, Adamu S, Derdeyn CP, Snyder AZ, Laforest R, Litzinger DC, Martin D, LeBel CP, Welch MJ: Positron emission tomography shows that intrathecal leptin reaches the hypothalamus in baboons. J Pharmacol Exp Ther. 2002, 307: 878-883. 10.1124/jpet.301.3.878.View ArticleGoogle Scholar
- During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN: Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003, 9: 1173-1179. 10.1038/nm919.View ArticlePubMedGoogle Scholar
- Frey WH: Bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord. Drug Deliv Technol. 2002, 2: 46-49.Google Scholar
- Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH, Craft S: Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired adults. J Alzheimers Dis. 2008, 13: 323-331.PubMed CentralPubMedGoogle Scholar
- Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W: Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004, 29: 1326-1334. 10.1016/j.psyneuen.2004.04.003.View ArticlePubMedGoogle Scholar
- Tyler BM, Jansen K, McCormick DJ, Douglas CL, Boules M, Stewart JA, Zhao L, Lacy B, Cusack B, Fauq A, Richelson E: Peptide nucleic acids targeted to the neurotensin receptor and administered i.p. cross the blood-brain barrier and specifically reduce gene expression. Proc Natl Acad Sci USA. 1999, 96: 7053-7058. 10.1073/pnas.96.12.7053.PubMed CentralView ArticlePubMedGoogle Scholar
- Banks WA, Farr SA, Butt W, Kumar VB, Franko MW, Morley JE: Delivery across the blood-brain barrier of antisense directed againt amyloid β: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein. J Pharmacol Exp Ther. 2001, 297: 1113-1121.PubMedGoogle Scholar
- Dogrukol-Ak D, Kumar VB, Ryerse JS, Farr SA, Verma S, Nonaka N, Nakamachi T, Ohtaki H, Niehoff ML, Edwards JC, Shioda S, Morley JE, Banks WA: Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer's and stroke models. J Cereb Blood Flow Metab. 2009, 29: 411-422. 10.1038/jcbfm.2008.131.View ArticlePubMedGoogle Scholar
- Urayama A, Grubb JH, Sly WS, Banks WA: Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier. Proc Natl Acad Sci USA. 2004, 101: 12658-12663. 10.1073/pnas.0405042101.PubMed CentralView ArticlePubMedGoogle Scholar
- Urayama A, Grubb JH, Sly WS, Banks WA: Mannose 6-phosphate receptor mediated transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther. 2008, 16: 1261-1266. 10.1038/mt.2008.84.PubMed CentralView ArticlePubMedGoogle Scholar
- Auclair D, Hopwood JJ, Brooks DA, Lemontt JF, Crawley AC: Replacement therapy for mucopolysaccharidosis type VI: advantages of early onset of therapy. Mol Genet Metab. 2003, 78: 163-174. 10.1016/S1096-7192(03)00007-6.View ArticlePubMedGoogle Scholar
- Gliddon BL, Hopwood JJ: Enzyme-replacement therapy from birth delays the development of behavior and learning problems in mucopolysaccharidosis type IIIA mice. Pediatr Res. 2004, 56: 1-8. 10.1203/01.PDR.0000129661.40499.12.View ArticleGoogle Scholar
- Vogler C, Levy B, Galvin NJ, Thorpe C, Sands MS, Barker JE, Baty J, Birkenmeier EH, Sly WS: Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy. Pediatr Res. 1999, 45: 838-844. 10.1203/00006450-199906000-00010.View ArticlePubMedGoogle Scholar
- Urayama A, Grubb JH, Banks WA, Sly WS: Epinephrine enhances lysosomal enzyme delivery across the blood-brain barrier by up-regulation of the mannos 6-phosphate receptor. Proc Natl Acad Sci USA. 2007, 31: 12873-12878. 10.1073/pnas.0705611104.View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.