Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy

Abstract

Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.

Recent advances in treatment for narcolepsy

“…33 A recent study showed that slow infusion of orexin delivered via a chronically implanted intrathecal catheter at the upper lumbar level in ORX knockout mice decreased cataplexy and sleep-onset REM sleep with unchanged sleep/wake states both quantitatively and qualitatively. 45 This study supports the concept of chronic intrathecal ORX delivery through an implantable pump as a potential therapy for refractory patients with NT1. A noninvasive method via intranasal administration of ORX (a method targeting drugs to the brain along the olfactory and trigeminal neural pathways) could also be of interest, with few preclinical and clinical data.…”

“…Orexin 45 This study supports the concept of chronic intrathecal ORX delivery through an implantable pump as a potential therapy for refractory patients with NT1. A noninvasive method via intranasal administration of ORX (a method targeting drugs to the brain along the olfactory and trigeminal neural pathways) could also be of interest, with few preclinical and clinical data.…”

Hypocretins (orexins): The ultimate translational neuropeptides

“…Since the peptides do not readily cross the blood-brain barrier, oral or intravenous (IV) administration routes are excluded. Intrathecal administration of Hcrt-1 is effective in treating cataplexy in narcoleptic Hcrt-KO mice [114] and may be a viable option in human narcolepsy, although it would require a combination of surgery and delivery device implantation.…”

Cataplexy

“…In particular, either intrathecal or intravenous delivery of hypocretin or an analogue can abolish cataplexy 32. There are considerable logistical problems in developing a suitable oral compound for human administration although early animal model data look promising 33…”