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Concomitant loss of dynorphin, NARP, and orexin in narcolepsy

From the Department of Neurology (A. Crocker and M. Papadopoulou, and Drs. España, Saper, and Scammell), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Psychiatry (Drs. Faraco, Honda, and Mignot), Stanford University Center for Narcolepsy, Palo Alto, CA; and Department of Pharmacology (Dr. Sakurai), Institute of Basic Medical Sciences, University of Tsukuba, Japan.

Address correspondence and reprint requests to Dr Scammell, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, Boston, MA 02115; e-mail: tscammel{at}bidmc.harvard.edu

Background: Narcolepsy with cataplexy is associated with a loss of orexin/hypocretin. It is speculated that an autoimmune process kills the orexin-producing neurons, but these cells may survive yet fail to produce orexin.

Objective: To examine whether other markers of the orexin neurons are lost in narcolepsy with cataplexy.

Methods: We used immunohistochemistry and in situ hybridization to examine the expression of orexin, neuronal activity-regulated pentraxin (NARP), and prodynorphin in hypothalami from five control and two narcoleptic individuals.

Results: In the control hypothalami, at least 80% of the orexin-producing neurons also contained prodynorphin mRNA and NARP. In the patients with narcolepsy, the number of cells producing these markers was reduced to about 5 to 10% of normal.

Conclusions: Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and neuronal activity-regulated pentraxin may contribute to the symptoms of narcolepsy.

Editorial, see page 1152

See also page 1189

This article was previously published in electronic format as an Expedited E-Pub on June 15, 2005, at www.neurology.org.

Supported by NIH grants MH62589 to T.S. and NS23724 to E.M.

Received December 30, 2004. Accepted in final form March 15, 2005.

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