Glutamate and NPY have been implicated in hippocampal neuropathology in temporal lobe epilepsy. Thus, we investigated the involvement of NPY receptors in mediating neuroprotection against excitotoxic insults in organotypic cultures of rat hippocampal slices. Exposure of hippocampal slice cultures to 2 µM AMPA (α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate) induced neuronal degeneration, monitored by propidium iodide uptake, of granule cells and CA1 pyramidal cells. For AMPA, whereas only the activation of Y2 receptors was effective for CA1 pyramidal cells. When the slice cultures were exposed to 6 µM kainate, the CA3 pyramidal cells displayed significant degeneration, and in this case the activation of Y1, Y2, and Y5 receptors was neuroprotective. For the kainic acid-induced degeneration of CA1 pyramidal cells, it was again found that only the Y2 receptor activation was effective. Based on the present findings, it was concluded that Y1, Y2, and Y5 receptors effectively can modify glutamate receptor-mediated neurodegeneration in the hippocampus.Key words: NPY • AMPA • kainate • neuroprotection • neurodegeneration N europeptide Y (NPY) is a 36-amino-acid peptide abundantly distributed in the brain and associated with a number of physiological and pathological conditions (1). This peptide has been shown to modulate anxiety, pain, memory, eating behavior, and many other functions in the central, as well as in the peripheral, nervous systems (1, 2). Another significant role of NPY that has become evident during the past decade is regulation of seizure activity (3).At least five NPY receptor subtypes have been identified based on different pharmacological profiles: Y1, Y2, Y4, Y5, and y6 (4). A putative Y3 receptor has also been identified (5 In the hippocampus, Y1 and Y2 receptors are highly expressed (11). Receptors of the Y1 subtype are preferentially located in granule cells of the dentate molecular layer, whereas Y2 receptors are expressed at high concentrations in the mossy fiber and Schaffer collateral fields (12). Moreover, Y5 receptor binding sites can also be found in the strata oriens and radiatum of the CA3 and CA1 areas (13,14). Presently, there is evidence for the involvement of these three NPY receptors subtypes in epilepsy. The activation of Y2 receptors suppresses seizure activity in hippocampal slices in vitro (15) and in vivo models (3). In human temporal lobe epilepsy, significant alterations in Y1 and Y2 receptor binding were observed (16). NPY Y5 receptors also seem to be involved in the suppression of seizure activity (17,18). In different animal models of epilepsy, NPY is highly expressed by granule cells and mossy fibers of the hippocampus (19,20), whereas in normal conditions only GABAergic interneurons express this peptide. Furthermore, knockout mice lacking the NPY gene develop spontaneous seizures and are more susceptible to pentylenetetrazol and kainic acid-induced motor seizures, which are inhibited by intracerebral infusion of NPY (21). Thus, these evidences suggest that N...