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Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route

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The choroid plexus (CP), i.e., the blood–cerebrospinal fluid barrier (BCSFB) interface, is an epithelial boundary exploitable for drug delivery to brain. Agents transported from blood to lateral ventricles are convected by CSF volume transmission (bulk flow) to many periventricular targets. These include the caudate, hippocampus, specialized circumventricular organs, hypothalamus, and the downstream pia–glia and arachnoid membranes. The CSF circulatory system normally provides micronutrients, neurotrophins, hormones, neuropeptides, and growth factors extensively to neuronal networks. Therefore, drugs directed to CSF can modulate a variety of endocrine, immunologic, and behavioral phenomema; and can help to restore brain interstitial and cellular homeostasis disrupted by disease and trauma. This review integrates information from animal models that demonstrates marked physiologic effects of substances introduced into the ventricular system. It also recapitulates how pharmacologic agents administered into the CSF system prevent disease or enhance the brain’s ability to recover from chemical and physical insults. In regard to drug distribution in the CNS, the BCSFB interaction with the blood–brain barrier is discussed. With a view toward translational CSF pharmacotherapy, there are several promising innovations in progress: bone marrow cell infusions, CP encapsulation and transplants, neural stem cell augmentation, phage display of peptide ligands for CP epithelium, CSF gene transfer, regulation of leukocyte and cytokine trafficking at the BCSFB, and the purification of neurotoxic CSF in degenerative states. The progressively increasing pharmacological significance of the CP–CSF nexus is analyzed in light of treating AIDS, multiple sclerosis, stroke, hydrocephalus, and Alzheimer’s disease.

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Acknowledgements

Concepts introduced or recapitulated in this article were stimulated by research funded by the Rhode Island Hospital (Lifespan), the Program in Neurosurgery at the Brown Medical School, the National Institutes of Health RO1 NS-27601 (CEJ), and BBSRC BB/C50466X (AB). We thank P. McMillan, A. Spangenberger, and V. Hovanesian for excellent electron microscopy and image analyses; and J. Johanson for graphical work. Our gratitude is also expressed to D. Smith for providing critique of the manuscript.

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  1. Conrad E. Johanson

    Present address: Department of Neurosurgery, Rhode Island Hospital, 593 Eddy Street (Aldrich 401), Providence, Rhode Island, 02903, USA

Authors and Affiliations

  1. Department of Clinical Neurosciences, Rhode Island Hospital, Brown Medical School, Providence, Rhode Island, 02912, USA

    Conrad E. Johanson & John A. Duncan

  2. Department of Pathology, Rhode Island Hospital, Brown Medical School, Providence, Rhode Island, 02912, USA

    Edward G. Stopa

  3. Human BioMolecular Research Institute, San Diego, California, 92121, USA

    Andrew Baird

  4. Molecular Neuroscience Group, School of Medicine, University of Birmingham, Edgbaston, UK

    Andrew Baird

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Correspondence to Conrad E. Johanson.

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Johanson, C.E., Duncan, J.A., Stopa, E.G. et al. Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route. Pharm Res 22, 1011–1037 (2005). https://doi.org/10.1007/s11095-005-6039-0

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