Peptide and peptide analog transport systems at the blood–CSF barrier
Introduction
A wide variety of naturally occurring peptides have been detected in cerebrospinal fluid (CSF) varying from small di- and tripeptides (e.g., carnosine and thyrotropin releasing hormone, TRH), to larger octa- and nonapeptides (e.g., vasopressin and angiotensin II), to large polypeptides (e.g., fibroblast growth factor-2, leptin, and insulin) [1], [2], [3]. Because such peptides may act as neuromodulators, there has been interest in how peptide concentrations are regulated and how they are affected by disease states, either as markers of disease or as potential modulators of injury [3], [4].
Many of the same factors that affect the brain disposition of naturally occurring peptides will also affect the disposition of exogenously delivered peptide or peptidomimetic drugs. Such factors include entry across the blood–brain and blood–CSF barriers (BCSFB) (diffusion and transport), efflux across the blood–brain and blood–CSF barriers, removal by CSF bulk flow and enzymatic degradation.
This review focuses on the particular role of the blood–CSF barrier (formed by the choroid plexus epithelial cells, Fig. 1, and the arachnoid membrane) and the CSF system in affecting peptide and peptidomimetic drug disposition. Section 2 focuses on general principles, Section 3 on polypeptide (≥4 amino acids) transport and secretion into CSF, while Section 4 examines the role of oligopeptide transport and, in particular, PEPT2.
Section snippets
General morphology of the cerebrospinal fluid system in relation to peptide transport
The choroid plexuses, situated in the lateral, third and fourth ventricles of mammals, are the main source of CSF secretion, although a small portion (10–30%) represents a bulk flow of brain interstitial fluid (ISF) from the brain parenchyma to CSF [5]. The CSF formed by the choroid plexuses flows out of the ventricular system into the subarachnoid space that surrounds the brain. From there, the fluid returns to the venous circulation either directly, via arachnoid villi in the venous sinuses,
Cerebrospinal fluid volume transmission of peptides and growth factors to the brain
Upon secretion into the ventricles, peptides and other macromolecules are conveyed by CSF bulk flow to various regions of the brain and spinal cord. Such bulk flow of fluid, driven by hydrostatic pressure gradients between large-cavity CSF and dural venous sinus blood, is also known as volume transmission [53], [54]. This convective distribution of peptide signals and trophic factors places many neurons in contact with the products and secretions of the choroid epithelial cells. Because CSF is
Molecular and functional features
In mammals, the proton-coupled oligopeptide transporter (POT) family consists of four members (i.e., PEPT1, PEPT2, PHT1, PHT2) and is responsible for the symport of small peptides/mimetics across biological membranes via an inwardly directed proton gradient and negative membrane potential. PEPT1 was first cloned from a rabbit intestinal cDNA library [130] and shown to be of high capacity and low affinity for di- and tripeptides [131], [132]. It is found primarily in the epithelia of intestine
Concluding remarks
Over the past few years, significant progress has been made in characterizing the transport mechanisms of oligopeptides, polypeptides, neuropeptides, and peptidomimetic drugs in choroid plexus. In particular, the cloning, membrane localization and functional activity of POT family members (e.g., PEPT2) have provided a basis for exploring transporter-based drug delivery and targeting strategies to the brain, and for appreciating new barriers at the blood–CSF interface. Still, there are critical
Acknowledgements
This work was supported in part by Grants R01 GM035498 (to D.E.S.), R01 NS027601 (to C.E.J.), and R01 NS034709 and P01 HL018575 (to R.F.K.) from the National Institutes of Health.
References (184)
- et al.
The fine structure of the choroid plexus: adult and developmental stages
Prog. Brain Res.
(1968) - et al.
A comprehensive analysis of the distribution of FGF-2 and FGFR1 in the rat brain
Brain Res.
(1995) - et al.
Leptin transport at the blood–cerebrospinal fluid barrier using the perfused sheep choroid plexus model
Brain Res.
(2001) - et al.
Leptin enters the brain by a saturable system independent of insulin
Peptides
(1996) - et al.
Differential distribution of messenger RNAs for cathepsins B, L and S in adult rat brain: an in situ hybridization study
Neuroscience
(1994) - et al.
Effect of histamine and antagonists on electrical resistance across the blood–brain barrier in rat brain-surface microvessels
Brain Res.
(1992) - et al.
Quantification of the permeability of the blood–CSF barrier to alpha-MSH in the rat
Peptides
(1984) - et al.
Immunocytochemical localization of cathepsin D in rat neural tissue
Brain Res.
(1981) - et al.
Aminopeptidase A: distribution in rat brain nuclei and increased activity in spontaneously hypertensive rats
Neuroscience
(1997) - et al.
An immunohistochemical study of endopeptidase-24.11 (“enkephalinase”) in the pig nervous system
Neuroscience
(1986)
Cytochemical study on enzyme activity associated with cerebrospinal fluid secretion in the choroid plexus and ventricular ependyma
Brain Res.
Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice
J. Biol. Chem.
Immuno-localization of H+/peptide cotransporter in rat digestive tract
Biochem. Biophys. Res. Commun.
Mammalian peptide transporters as targets for drug delivery
Trends Pharmacol. Sci.
A morphometric study on the development of the lateral choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat
Dev. Brain Res.
Cortical microvessels during brain development: a morphometric study in the rat
Microvasc. Res.
Diffusion of molecules in brain extracellular space: theory and experiment
Prog. Brain Res.
Storage, metabolism, and processing of 125I-fibroblast growth factor-2 after intracerebral injection
Brain Res.
Characterization of putative growth hormone receptors in human choroid plexus
Brain Res.
Localization and ontogeny of growth hormone receptor gene expression in the central nervous system
Brain Res. Dev. Brain Res.
Detection of growth hormone receptor mRNA in an ovine choroid plexus epithelium cell line
Biochem. Biophys. Res. Commun.
Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance
Front. Neuroendocrinol.
Passage of delta sleep-inducing peptide (DSIP) across the blood–cerebrospinal fluid barrier
Peptides
Decreased transport of leptin across the blood–brain barrier in rats lacking the short form of the leptin receptor
Peptides
Differential expression of the two forms of prolactin receptor mRNA within microdissected hypothalamic nuclei of the rat
Brain Res. Mol. Brain Res.
Effects of advancing age on cerebrospinal fluid concentrations of prolactin in the female rat
Brain Res.
The presence of arginine vasopressin and its mRNA in rat choroid plexus epithelium
Brain Res. Mol. Brain Res.
Distribution and cellular localization of vasopressin mRNA in the ovine brain, pituitary and pineal glands
Neuropeptides
The inhibition of fibroblast growth factor-2 export by cardenolides implies a novel function for the catalytic subunit of Na+, K+-ATPase
J. Biol. Chem.
Salt-loading increases vasopressin and vasopressin 1b receptor mRNA in the hypothalamus and choroid plexus
Neuropeptides
Vasopressin in the cerebrospinal fluid of febrile children with or without seizures
Brain Dev.
Neuroendocrinology of cerebrospinal fluid: peptides, steroids and other hormones
Neurosurgery
Physiology and Pathophysiology of the Cerebrospinal Fluid
The Blood–Brain Barrier, Amino Acids and Peptides
Neuropeptides in neurological disease
Ann. Neurol.
Convection of brain interstitial fluid
Drainage of cerebral interstitial and of cerebrospinal fluid into lymphatics
Junctions between intimately apposed cell membranes in the vertebrate brain
J. Cell Biol.
The Concept of a Blood–Brain Barrier
Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats
Exp. Brain Res.
The nature of the decrease in blood–cerebrospinal fluid barrier exchange during postnatal brain development in the rat
J. Physiol.
Determination of acid surface pH in vivo in rat proximal jejunum
Gut
Membrane peptidases in the pig choroid plexus and on other cell surfaces in contact with the cerebrospinal fluid
Biochem. J.
Choroid plexus Na+/K+-activated adenosine triphosphatase and cerebrospinal fluid formation
Neurosurgery
Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood–cerebrospinal fluid barrier
J. Clin. Invest.
Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood–cerebrospinal-fluid drug permeability barrier
Proc. Natl. Acad. Sci. U. S. A.
Choroid plexus: target for polypeptides and site of their synthesis
Microsc. Res. Tech.
Vasopressin gene expression in rat choroid plexus
Adv. Exp. Med. Biol.
Differential regulation of leptin transport by the choroid plexus and blood–brain barrier and high affinity transport systems for entry into hypothalamus and across the blood–cerebrospinal fluid barrier
Endocrinology
The expression of tripeptidyl peptidase I in various tissues of rats and mice
Arch. Histol. Cytol.
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