1. ¹Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey
2. ²GRECC, Veterans Affairs Medical Center-Saint Louis, St Louis, Missouri, USA
3. ³Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USA
4. ⁴Department of Pathology, Saint Louis University Health Sciences Center, St Louis, Missouri, USA
5. ⁵Department of Oral Anatomy, Showa University School of Dentistry, Tokyo, Japan
6. ⁶Department of 1st Anatomy, Showa University School of Medicine, Tokyo, Japan
7. ⁷Department of Nephrology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

Correspondence: Professor WA Banks, GRECC, Veterans Affairs Medical Center-Saint Louis, 915 N Grand Boulevard, St Louis, MO 63106, USA. E-mail: bankswa@slu.edu

Received 13 August 2008; Revised 8 September 2008; Accepted 8 October 2008; Published online 12 November 2008.

Abstract

By isolating for the first time ever a peptide transporter from the blood–brain barrier (BBB) and developing an antisense that selectively targets the brain-to-blood efflux component, we were able to deliver a therapeutic concentration of the neurotrophic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) 27 to brain in animal models of Alzheimer's and stroke. Efflux pumps at the BBB are major causes of BBB impermeability to peptides. PACAP is neuroprotective in vitro in femtomole amounts, but brain uptake of PACAP27 is limited by an efflux component of peptide transport system-6 (PTS-6). Here, we characterized, isolated, and sequenced this component of PTS-6, identifying it as -F1 ATPase, and colocalized it with PACAP27 on BBB endothelial cells. Antisenses targeting the BBB inhibited PACAP27 efflux, thus increasing brain uptake of PACAP27. Treatment with antisense+PACAP27 improved cognition in a mouse model of Alzheimer's disease and reduced infarct size after cerebral ischemia. This represents the first isolation from BBB tissue of a peptide transporter and shows that inhibition of peptide efflux pumps is a potential strategy for drug delivery to brain.