(Background and Methods) Two novel hypothalamic neuropeptides, orexin-A (hypocretin-1) and orexin-B (hypocretin-2), have recently been identified. Subsequent studies discovered that a chronic human sleep disorder, namely narcolepsy, is specifically associated with a reduced production of the hypocretin/orexin peptides in the hypothalamus. This orexin/hypocretin deficiency in the brain of narcoleptics has been clinically detected to demonstrate either reduced or undetectably low orexin-A/hypocretin-1 levels in the CSF. Orexins/hypocretins were initially characterized as potent stimulants of food intake, but they have also been shown to be involved in various hypothalamic functions, including energy homeostasis, neuroendocrine and autonomic nervous system functions, pain perception and vigilance control. Orexin/ hypocretin may also be involved in various neurological conditions associated with hypothalamic dysfunctions, and reduced CSF orexin-A/hypocretin-1 levels have been reported to occur in subsets of patients with brain tumors, neurotrauma, vascular diseases, infections, Parkinson's disease and Guillain? Barré syndrome, as well as symptomatic cases of narcolepsy due to various underlying causes. The aim of this study was to examine the role of the hypothalamic orexin-A/hypocretin-1 system in patients with hemorrhagic stroke (SAH and ICH) patients. (Results and Conclusions) CSF orexin-A/hypocretin-1 levels were low both in SAH and ICH patients. In SAH patients, CSF hypocretin-1/orexin-A levels were lower in patients with symptomatic vasospasms complications than in those who did not develop. In ICH patients, the CSF orexin-A/hypocretin-1 levels were lower in the thalamic hemorrhage patients than those in other patients. These data suggest that a reduction in hypocretin/orexin production in hemorrhagic stroke patients is associated with alterations in brain hypocretin/orexin signaling in response to ischemia and hypothalamic dysfunction. In the current study, we also refer to the time-dependent changes in cerebrospinal fluid (CSF) orexin-A concentration and the expression of the orexin-1 receptor (OX1R) in the rat hippocampus after global ischemia-reperfusion (5 min cardiopulmonary arrest).