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

Mahesh K. Kaushik, Kosuke Aritake, Aya Imanishi, Takashi Kanbayashi, Tadashi Ichikawa, Tetsuo Shimizu, Yoshihiro Urade, Masashi Yanagisawa

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6046-6051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number23
DOIs
StatePublished - Jun 5 2018

Keywords

  • Lumbar spinal cord
  • Non-REM sleep
  • Orexin knockout mice
  • Slow infusion

ASJC Scopus subject areas

  • General

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