Neuropeptide Y (NPY), a 36 amino acid peptide widely distributed in the nervous system, inhibits glutamatergic transmission and decreases hippocampal epileptiform activity which may lead to neuroprotection. Such effects were observed in some earlier studies, but results are divergent and the role of particular Y receptors remains unclear. In the present study we investigated a possibility of neuroprotective action of neuropeptide Y1, Y2 and Y5 receptor specifi c ligands in rats in two in vivo models of brain damage. In the fi rst model, kainic acid (KA)(2.5 nmol/1 μl) was microinjected into the CA1 region of the rat dorsal hippocampus and the peptide compounds (470 pmol/1 μl) were injected in the same region 30 min, 1 h or 3 h after the kainate. Seven days later the brains were taken for histology and number of neurons in CA pyramidal layer was evaluated by stereological counting. It was found that, Y2 agonist (NPY13- 36) and Y5R agonist ([CPP1-17,NPY19-23,Ala31,Aib32Gln34] hPP), injected 30 min or 1 h but not 3 h after the KA, signifi cantly diminished KA-induced hippocampal lesion. Contrary Y1 agonist ([Leu31,Pro34]-NPY) did not induced any protection but had a tendency towards an increase of the degeneration. The most promising Y2 agonist was tested also in the second model, focal cerebral ischemia after transient middle cerebral artery occlusion (MCAO). The peptide was injected icv (10 μg/6 μl,), 30 min after MCA occlusion. It signifi cantly diminished MCAO-induced brain damage evaluated by TTC staining. Our results indicated neuroprotective effects of Y2 and Y5 activation. Moreover we found that the peptides may be effective after delayed (30ñ60 min) application.