Propionyl-IIGL tetrapeptide antagonizes beta-amyloid excitotoxicity in rat nucleus basalis.
A putative tetrapeptide beta-amyloid (Abeta) antagonist (propionyl-Ile-Ile-Gly-Leu [Pr-IIGL]) based on the [31-34] sequence of Abeta was previously shown to rescue astrocytes from Abeta-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 effectively attenuates the excitotoxic action of Abeta(1-42) on cholinergic neurons of the rat magnocellular nucleus basalis (MBN). We also demonstrate by means of microdialysis that administration of Pr-IIGL abolished Abeta(1-42)-induced increases in extracellular aspartate and glutamate concentrations in the MBN, 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, modified functional Abeta antagonists in ameliorating Abeta excitotoxicity in vivo.
Harkany
T
T
Department of Animal Physiology, University of Groningen, Haren, The Netherlands.
Abrahám
I
I
Laskay
G
G
Timmerman
W
W
Jost
K
K
Zarándi
M
M
Penke
B
B
Nyakas
C
C
Luiten
P G
PG
D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects; D020532:Basal Nucleus of Meynert / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006651:Histocytochemistry; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C106796:propionyl-isoleucyl-isoleucyl-glycyl-leucinamide; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D000110:Acetylcholinesterase