Orexins promote survival of rat cortical neurons

Abstract Orexin A and B (hypocretin-1 and -2) are hypothalamic peptides that exert their biological functions by stimulation of two specific, membrane-bound receptors, OX 1 R and OX 2 R. Recently, we have demonstrated the expression of both types of orexin receptors in rat cortical neurons, with the OX 2 R level being markedly higher compared to OX 1 R. In the present study we investigated the receptor-mediated effects of orexin A, an agonist of OX 1 R and OX 2 R, orexin B and [Ala 11 - D -Leu 15 ]orexin B, preferential agonists of OX 2 R, on survival of cultured neurons derived from rat cerebral cortex. The three tested peptides markedly increased neuronal viability in a concentration-dependent manner. The pro-survival properties of orexins were associated with an attenuation of caspase-3 activity. Comparable potency of orexin A, orexin B and [Ala 11 - D -Leu 15 ]orexin B suggests a predominant role of OX 2 R in the studied phenomenon. Our findings provide new insights into the role of orexins in CNS as potential neuroprotective factors.