RT Journal Article
SR Electronic
T1 Protective Peptides That Are Orally Active and Mechanistically Nonchiral
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1190
OP 1197
DO 10.1124/jpet.103.063891
VO 309
IS 3
A1 Douglas E. Brenneman
A1 Catherine Y. Spong
A1 Janet M. Hauser
A1 Daniel Abebe
A1 Albert Pinhasov
A1 Tania Golian
A1 Illana Gozes
YR 2004
UL http://jpet.aspetjournals.org/content/309/3/1190.abstract
AB 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 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. The American Society for Pharmacology and Experimental Therapeutics