Orexins promote survival of rat cortical neurons

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.