Protective peptides that are orally active and mechanistically nonchiral

Douglas E. Brenneman*, Catherine Y. Spong, Janet M. Hauser, Daniel Abebe, Albert Pinhasov, Tania Golian, Illana Gozes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 β-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 I 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-NAPV-SIPQ 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.

Original languageEnglish
Pages (from-to)1190-1197
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume309
Issue number3
DOIs
StatePublished - Jun 2004

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