Megan Brooks

June 12, 2013

BALTIMORE, Maryland — Researchers have unexpectedly found an increase in histaminergic neurons in patients with narcolepsy, a finding that may have therapeutic implications.

Narcolepsy is caused by a loss of hypothalamic neurons that produce the orexin/hypocretin neuropeptides, which promote wakefulness. The new study shows narcolepsy is also associated with a "very large" increase in the number of neurons producing histamine, another wake-promoting neurotransmitter, principal investigator Thomas Scammell, MD, professor of neurology at Beth Israel Deaconess Medical Center in Boston, Massachusetts, said in a statement.

Philipp Valko, MD, also from Beth Israel Deaconess Medical Center and from University Hospital Zurich, Switzerland, presented the research at SLEEP 2013: Associated Professional Sleep Societies 27th Annual Meeting.

Compensatory Mechanism?

Using stereologic techniques, the study team counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone (MCH), and histamine in 7 patients with narcolepsy and 12 control patients.

They found that compared with controls, patients with narcolepsy had 94% more histaminergic neurons (233,572 vs 120,455; P < .001). This increase was more pronounced in 5 patients with narcolepsy who had severe orexin neuron loss than in 2 patients with less severe loss, the researchers say.

The results were similar in mouse models, where the number of histaminergic neurons was increased 53% in orexin ligand knockout mice compared with wild-type mice, while orexin/ataxin-3 transgenic mice showed an intermediate 28% increase.

The researchers say this "surprising" increase in wake-promoting histaminergic neurons in patients with narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons.

Nathaniel Watson, MD, neurologist and sleep specialist with University of Washington, Seattle, who wasn't involved in the study, agrees.

"Histamine is a key component of the monoaminergic arousal system in the brain. Increases in histaminergic cells in the hypothalamus of narcolepsy patients suggest attempts at compensating for orexin cell loss to increase alertness to predisease levels in these patients," he told Medscape Medical News.

Increases in histaminergic neurons in narcolepsy may also contribute to some of the symptoms of narcolepsy, such as preserved consciousness during cataplexy and fragmented nighttime sleep, the investigators say.

Promising Drug Target

"Previous studies have assumed that loss of the orexin neurons was a sufficient explanation for the symptoms of narcolepsy, and this large increase in histamine-producing neurons was unexpected," Dr. Scammell noted.

"This new observation suggests that drugs that reduce histamine signaling at night may improve sleep in narcolepsy, whereas drugs that enhance histamine signals may be a good option for promoting alertness during the day," he added. Medications that enhance histamine are now under development.

The study was supported by the Swiss National Science Foundation. The authors and Dr. Watson have disclosed no relevant financial relationships.

SLEEP 2013: Associated Professional Sleep Societies 27th Annual Meeting. Abstract Presented June 3, 2013.

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