ABSTRACT
Hypocretin-1 (HC, orexin-A) is a neuropeptide involved in regulating physiological functions of sleep, appetite and arousal, and it has been shown that intranasal (IN) administration can target HC to the brain. Recent clinical studies have shown that IN HC has functional effects in human clinical trials. In this study, we use rats to determine whether IN HC has an immediate effect on food consumption and locomotor activity, whether distribution in the brain after IN delivery is dose-dependent, and whether MAPK and PDK1 are affected after IN delivery. Food intake and wheel-running activity were quantified for 24h after IN delivery. Biodistribution was determined 30min after IN delivery of both a high and low dose of 125I-radiolabelled HC throughout the brain and other bodily tissues, while Western blots were used to quantify changes in cell signaling pathways (MAPK and PDK1) in the brain. Intranasal HC significantly increased food intake and wheel activity within 4h after delivery, but balanced out over the course of 24h. The distribution studies showed dose-dependent delivery in the CNS and peripheral tissues, while PDK1 was significantly increased in the brain 30min after IN delivery of HC. This study adds to the growing body of evidence that IN administration of HC is a promising strategy for treatment of HC related behaviors.
Subject(s)
Eating/drug effects , Motor Activity/drug effects , Orexins/administration & dosage , Administration, Intranasal , Animals , Brain Chemistry , Drinking/drug effects , Male , Mitogen-Activated Protein Kinase 1/metabolism , Orexins/analysis , Protein Serine-Threonine Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Rats, Sprague-Dawley , Signal Transduction , Spinal Cord/chemistryABSTRACT
BACKGROUND: The presence of osmotic gradients in the development of cerebral edema and the effectiveness of osmotherapy are well recognized. A modification of ventriculostomy catheters described in this article provides a method of osmotherapy that is not currently available. The reductive ventricular osmotherapy (RVOT) catheter removes free water from ventricular cerebrospinal fluid (CSF) by incorporating hollow fibers that remove water vapor, thereby providing osmotherapy without increasing osmotic load. OBJECTIVE: To increase osmolarity in the ventricular CSF through use of RVOT in vivo. METHODS: Twelve Yorkshire swine with contusional injury were randomized to external ventricular drainage (EVD) or RVOT for 12 hours. MR imaging was obtained. Serum, CSF, and brain ultrafiltrate were analyzed. Histology was compared using Fluor-Jade B and hematoxylin and eosin (H & E) stains. RESULTS: With RVOT, CSF osmolality increased from 292 ± 2.7 to 345 ± 8.0 mOsmol/kg (mean ± SE, P = 0.0006), and the apparent diffusion coefficient (ADC) in the injury region increased from 0.735 ± 0.047 to 1.135 ± .063 (P = 0.004) over 24 hours. With EVD controls, CSF osmolarity and ADC were not significantly changed. Histologically, all RVOT pigs showed no evidence of neuronal degeneration (Grade 1/4) compared to moderate degeneration (Grade 2.6 ± .4/4) seen in EVD treated animals (P = 0.02). The difference in intracranial pressure (ICP) by area under the curve approached significance at P = .065 by Mann Whitney test. CONCLUSION: RVOT can increase CSF osmolarity in vivo after experimental traumatic brain injury (TBI). In anticipated clinical use, only a slight increase in CSF osmolarity may be required to reduce cerebral edema.
