QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.063891v1 309/3/1190    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brenneman, D. E. Articles by Gozes, I. Search for Related Content PubMed PubMed Citation Articles by Brenneman, D. E. Articles by Gozes, I.

TOXICOLOGY

Protective Peptides That Are Orally Active and Mechanistically Nonchiral

Section on Developmental and Molecular Pharmacology, Laboratory of Developmental Neurobiology (D.E.B., J.M.H., D.A.) and Pregnancy and Perinatology Branch (C.Y.S.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; and Department of Clinical Biochemistry (A.P., T.G., I.G.), Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Previous reports identified two peptides that mimic the action of neuroprotective proteins derived from astrocytes. These peptides, NAPVSIPQ and SALLRSIPA, prevent neuronal cell death produced by electrical blockade, N-methyl-D-aspartate, and -amyloid peptide (25-35). In the present study, all D-amino acid peptides of NAPVSIPQ and SALLRSIPA were synthesized and compared respectively to the corresponding all L-amino acid peptides. In rat cerebral cortical test cultures cotreated with 1 µM tetrodotoxin, the D-amino acid peptides produced similar potency and efficacy for neuroprotection as that observed for their respective L-amino acid peptides. Since all these peptides tested individually exhibited attenuation of efficacy at concentrations of >10 pM, combinations of these peptides were tested for possible synergies. Equimolar D-NAPVSIPQ and D-SALLRSIPA combination treatment produced potent neuroprotection (EC₅₀, 0.03 fM) that did not attenuate with increasing concentrations. Similarly, the combination of L-NAPVSIPQ and D-SALLRSIPA also had high potency (EC₅₀, 0.07 fM) without attenuation of efficacy. Combined administration of peptides was tested in a model of fetal alcohol syndrome and in a model of learning impairment: apolipoprotein E knockout mice. Intraperitoneal administration of D-NAPVSIPQ plus D-SALLRSIPA to pregnant mice (embryonic day 8) attenuated fetal demise after treatment with an acute high dose of alcohol. Furthermore, oral administration of D-NAPVSIPQ plus D-SALLRSIPA significantly increased fetal survival after maternal alcohol treatment. Apolipoprotein E knockout mice injected with D-NAPVSIPQ plus D-SALLRSIPA showed improved performance in the Morris water maze. These studies suggest therapeutic potential for the combined administration of neuroprotective peptides that can act through a mechanism independent of chiral recognition.

Address correspondence to: Douglas E. Brenneman, Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, Spring House, PA 19477. E-mail address: dbrennem{at}prdus.jnj.com

This article has been cited by other articles:

				L. Visochek, R. A. Steingart, I. Vulih-Shultzman, R. Klein, E. Priel, I. Gozes, and M. Cohen-Armon PolyADP-Ribosylation Is Involved in Neurotrophic Activity J. Neurosci., August 10, 2005; 25(32): 7420 - 7428. [Abstract] [Full Text] [PDF]

				I. Divinski, L. Mittelman, and I. Gozes A Femtomolar Acting Octapeptide Interacts with Tubulin and Protects Astrocytes against Zinc Intoxication J. Biol. Chem., July 2, 2004; 279(27): 28531 - 28538. [Abstract] [Full Text] [PDF]