NeuropharmacologyPropionyl-IIGL tetrapeptide antagonizes β-amyloid excitotoxicity in rat nucleus basalisHarkany, Tibor1,2,6; ÁbraháAm, István3; Laskay, Gábor5; Timmerman, Wia4; Jost, Krisztina5; Zarándi, Márta5; Penke, Botond5; Nyakas, Csaba1,2; M. Luiten, Paul G.1Author Information 1Department of Animal Physiology, University of Groningen, P.O. Box 14, Kerklaan 30, 9750 AA Haren, The Netherlands 2Central Research Division, Haynal University of Health Sciences, Budapest, Hungary 3Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary 4Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, The Netherlands 5Department of Medical Chemistry, Szent-Györgyi Albert Medical University, Szeged, Hungary 6Corresponding Author and Address: Tibor Harkany, Department of Animal Physiology, University of Groningen, P.O. Box 14, Kerklaan 30, 9750 AA Haren, The Netherlands ACKNOWLEDGEMENTS: The authors thank Dr Gábor Juhász and Dr Málria Sasvári for their expert help during the initial phase of microdialysis experiments. This work was supported by OTKA, Hungary (F23865 to T.H., F016560 to. I.A Á., T017751 to P.B., T022546 to M.Z., T026451 to C.N., T022542 to L.G.) and a joint grant of NWO and OTKA (NWO 048-11-006 to P.G.M. L./OTKA N26674 to C.N.). Received 24 February 1999; accepted 13 April 1999 NeuroReport: June 3rd, 1999 - Volume 10 - Issue 8 - p 1693-1698 Buy Abstract A putative tetrapeptide β-amyloid (Aβ) antagonist (propionyl-Ile-Ile-Gly-Leu [Pr-IIGL]) based on the [31–34] sequence of Aβ was previously shown to rescue astrocytes from Aβ-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 Aβ(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 Aβ(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 Aβ antagonists in ameliorating Aβ excitotoxicity in vivo. © 1999 Lippincott Williams & Wilkins, Inc.