Elsevier

Advanced Drug Delivery Reviews

Volume 56, Issue 12, 14 October 2004, Pages 1765-1791
Advanced Drug Delivery Reviews

Peptide and peptide analog transport systems at the blood–CSF barrier

https://doi.org/10.1016/j.addr.2004.07.008Get rights and content

Abstract

In addition to being the main source of cerebrospinal fluid (CSF) secretion, the choroid plexuses are involved in the supply and distribution of peptides to brain, the removal of toxic metabolites, the excretion of xenobiotics, and the delivery of drugs as an alternative route to the blood–brain barrier (BBB). The discovery of proton-coupled oligopeptide transporters in choroid plexus has generated considerable interest regarding their physiologic role at the blood–cerebrospinal fluid interface and their potential for peptide/antagonist pharmacotherapy in the central nervous system. Many of the same factors that affect the disposition of naturally occurring peptides in brain will also affect the disposition of exogenously delivered peptide or peptidomimetic drugs. Therefore, this review addresses three main areas: (1) choroid plexus structure, physiology, and barrier function in relation to peptide transport; (2) polypeptide transport and secretion mechanisms into cerebrospinal fluid; and (3) molecular physiology, expression, and functional activity of proton-coupled oligopeptide transporters in choroid plexus.

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)

  • T. Masuzawa et al.

    Cytochemical study on enzyme activity associated with cerebrospinal fluid secretion in the choroid plexus and ventricular ependyma

    Brain Res.

    (1981)
  • D.H. Sweet et al.

    Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice

    J. Biol. Chem.

    (2002)
  • H. Ogihara et al.

    Immuno-localization of H+/peptide cotransporter in rat digestive tract

    Biochem. Biophys. Res. Commun.

    (1996)
  • I. Rubio-Aliaga et al.

    Mammalian peptide transporters as targets for drug delivery

    Trends Pharmacol. Sci.

    (2002)
  • R.F. Keep et al.

    A morphometric study on the development of the lateral choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat

    Dev. Brain Res.

    (1990)
  • R.F. Keep et al.

    Cortical microvessels during brain development: a morphometric study in the rat

    Microvasc. Res.

    (1990)
  • C. Nicholson et al.

    Diffusion of molecules in brain extracellular space: theory and experiment

    Prog. Brain Res.

    (2000)
  • A.M. Gonzalez et al.

    Storage, metabolism, and processing of 125I-fibroblast growth factor-2 after intracerebral injection

    Brain Res.

    (1994)
  • Z.N. Lai et al.

    Characterization of putative growth hormone receptors in human choroid plexus

    Brain Res.

    (1991)
  • P.E. Lobie et al.

    Localization and ontogeny of growth hormone receptor gene expression in the central nervous system

    Brain Res. Dev. Brain Res.

    (1993)
  • M. Thornwall et al.

    Detection of growth hormone receptor mRNA in an ovine choroid plexus epithelium cell line

    Biochem. Biophys. Res. Commun.

    (1995)
  • F. Nyberg

    Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance

    Front. Neuroendocrinol.

    (2000)
  • B.V. Zlokovic et al.

    Passage of delta sleep-inducing peptide (DSIP) across the blood–cerebrospinal fluid barrier

    Peptides

    (1988)
  • A.J. Kastin et al.

    Decreased transport of leptin across the blood–brain barrier in rats lacking the short form of the leptin receptor

    Peptides

    (1999)
  • X.J. Pi et al.

    Differential expression of the two forms of prolactin receptor mRNA within microdissected hypothalamic nuclei of the rat

    Brain Res. Mol. Brain Res.

    (1998)
  • J.W. Simpkins

    Effects of advancing age on cerebrospinal fluid concentrations of prolactin in the female rat

    Brain Res.

    (1992)
  • A. Chodobski et al.

    The presence of arginine vasopressin and its mRNA in rat choroid plexus epithelium

    Brain Res. Mol. Brain Res.

    (1997)
  • S.G. Matthews et al.

    Distribution and cellular localization of vasopressin mRNA in the ovine brain, pituitary and pineal glands

    Neuropeptides

    (1993)
  • R.Z. Florkiewicz et al.

    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.

    (1998)
  • D.A. Zemo et al.

    Salt-loading increases vasopressin and vasopressin 1b receptor mRNA in the hypothalamus and choroid plexus

    Neuropeptides

    (2001)
  • T. Kiviranta et al.

    Vasopressin in the cerebrospinal fluid of febrile children with or without seizures

    Brain Dev.

    (1996)
  • J.H. Wood

    Neuroendocrinology of cerebrospinal fluid: peptides, steroids and other hormones

    Neurosurgery

    (1982)
  • H. Davson et al.

    Physiology and Pathophysiology of the Cerebrospinal Fluid

    (1987)
  • M.B. Segal et al.

    The Blood–Brain Barrier, Amino Acids and Peptides

    (1990)
  • M.F. Beal et al.

    Neuropeptides in neurological disease

    Ann. Neurol.

    (1986)
  • H. Cserr

    Convection of brain interstitial fluid

  • M.W.B. Bradbury et al.

    Drainage of cerebral interstitial and of cerebrospinal fluid into lymphatics

  • M.W. Brightman et al.

    Junctions between intimately apposed cell membranes in the vertebrate brain

    J. Cell Biol.

    (1969)
  • M.W.B. Bradbury

    The Concept of a Blood–Brain Barrier

    (1979)
  • R.K. Ferguson et al.

    Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats

    Exp. Brain Res.

    (1969)
  • M.D. Habgood et al.

    The nature of the decrease in blood–cerebrospinal fluid barrier exchange during postnatal brain development in the rat

    J. Physiol.

    (1993)
  • M. Lucas

    Determination of acid surface pH in vivo in rat proximal jejunum

    Gut

    (1983)
  • A. Bourne et al.

    Membrane peptidases in the pig choroid plexus and on other cell surfaces in contact with the cerebrospinal fluid

    Biochem. J.

    (1989)
  • M. Pollay et al.

    Choroid plexus Na+/K+-activated adenosine triphosphatase and cerebrospinal fluid formation

    Neurosurgery

    (1985)
  • J. Wijnholds et al.

    Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood–cerebrospinal fluid barrier

    J. Clin. Invest.

    (2000)
  • V.V. Rao et al.

    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.

    (1999)
  • A. Chodobski et al.

    Choroid plexus: target for polypeptides and site of their synthesis

    Microsc. Res. Tech.

    (2001)
  • A. Chodobski et al.

    Vasopressin gene expression in rat choroid plexus

    Adv. Exp. Med. Biol.

    (1998)
  • B.V. Zlokovic et al.

    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

    (2000)
  • M. Koike et al.

    The expression of tripeptidyl peptidase I in various tissues of rats and mice

    Arch. Histol. Cytol.

    (2002)
  • Cited by (150)

    • Finding a cell-permeable compound to inhibit inflammatory cytokines: Uptake, biotransformation, and anti-cytokine activity of javamide-I/-II esters

      2022, Life Sciences
      Citation Excerpt :

      These data suggest that javamide-I/-II esters can be transported better than the parent compounds and the uptake of the esters can be affected by the chemical structures of phenylpropenoic acids (e.g., coumaric acid and caffeic acids). Because PepT1/2 transporters are known to transport small peptide-like compounds [20,21], and because monocyte/macrophage-like cells including THP-1 were reported to express PepT2 [20–22], the involvement of PepT2 in the ester uptake was investigated using GlySar, because GlySar is a known proton-coupled peptide transporter substrate [24–27]. For this experiment, javamide-I ester was selected to determine the inhibition by GlySar, because javamide-I ester uptake was higher than javamide-II ester.

    • Transport of ions across the choroid plexus epithelium

      2022, Cerebrospinal Fluid and Subarachnoid Space: Clinical Anatomy and Physiology: Volume 1
    • Alternate expression of PEPT1 and PEPT2 in epidermal differentiation is required for NOD2 immune responses by bacteria-derived muramyl dipeptide

      2020, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      PEPT1 is predominantly expressed in the intestinal epithelium and functions for absorption of dietary nutrients [2,3]. PEPT2 is widely expressed in other tissues and has been reported to function in the kidney in reabsorption of dietary peptides [4,5]. These two peptide transporters have some differences in terms of substrate affinity and capacity.

    View all citing articles on Scopus
    View full text