Orexins (hypocretins) are hypothalamic peptides present in neurons that project throughout the brain. They act through two receptors: OX1 and OX2. Recently, it has been demonstrated that orexins exert potent proapoptotic activity in various cancer cell lines. On the other hand, little is known about the role of these peptides in survival of neurons and their supportive cells in the brain. Therefore, the aim of our study was to investigate whether orexins are implicated in receptor-mediated survival- or deathpromoting effects in cultured neurons and astrocytes derived from rat cerebral cortex. Real-time PCR experiments indicated that both types of orexin receptors were expressed in rat neurons and astrocytes. In cultured neurones OX2R expression was considerably higher than that of OX1R. In astrocytes similar expressions of both types of orexin receptors were identified but they were markedly lower compared to neurons. Incubation of primary neuronal cultures with orexin A, orexin B and [Ala11-D-Leu15]orexin B (a selective agonist of OX2R) resulted in a marked increase of cells viability and a parallel reduction of apoptotic cells as assessed by MTT test and caspase-3 assay kit. In cultured astrocytes the tested neuropeptides increased cell viability (MTT) and stimulated 3 H-thymidine incorporation but had no effect on caspase-3 activity, an observation indicating that orexins may affect astrocytes survival by enhancing cell proliferation. In the next set of experiments cultured neurons were subjected to hypoxia induced chemically by iron chelator cobalt chloride. Orexins A and B, and [Ala11-D-Leu15]orexin B effectively protected neuronal cells, suggesting that the peptides may be endowed with neuroprotective potential in the brain. Supported by MNiSW (grant No 4254/B/ PO1/2010/38) and InterMolMed (grant No POIG.01.01.02-10- 107/09).
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