A putative tetrapeptide beta-amyloid (A beta) antagonist (propionyl-Ile-Ile
-Gly-Leu [Pr-IIGL]) based on the [31-34] sequence of A beta was previously
shown to rescue astrocytes from A beta-induced membrane depolarization and
subsequent long-term elevations of the intracellular Ca2+ concentration in
vitro. Here we provide in vivo evidence that the Pr-IIGL tetrapeptide effec
tively attenuates the excitotoxic action of A beta(1-42) on cholinergic neu
rons of the rat magnocellular nucleus basalis (MBN). We also demonstrate by
means of microdialysis that administration of Pr-IIGL abolished A beta(1-4
2)induced increases in extracellular aspartate and glutamate concentrations
in the MEN, which coincide with a significant preservation of cholinergic
MBN neurons and their cortical projections. This neuroprotective effect was
associated with preserved exploratory behavior in an open-field paradigm,
and improved memory retention in a step-through passive avoidance task. Our
data presented here indicate for the first time the efficacy of short, mod
ified functional A beta antagonists in ameliorating A beta excitotoxicity i
n vivo. NeuroReport 10:1693-1698 (C) 1999 Lippincott Williams & Wilkins.