Summary: Researchers believe compound could help cure narcolepsy.
Source: University of Tsukuba.
The first step to deliver a magic bullet for curing narcolepsy.
Narcolepsy, a serious sleep disorder in which patients often fall asleep uncontrollably, has been incurable because no effective therapeutic agents are available to date. Recent findings by Japanese scientists in the sleep institute may shed light on this challenging problem.
Narcolepsy is characterized by excessive daytime sleepiness (sleep attacks), sudden loss of muscle tone often triggered by emotion (called cataplexy), vivid hallucinations and sleep paralysis, and frequent disruption of night-time sleep. Only symptomatic therapies, such as amphetamine-like psychostimulants, are currently available. The disease is caused by a selective loss of neurons producing the neuropeptide orexin, which plays a central role in maintaining wakefulness. Orexin itself is effective to ameliorate narcoleptic symptoms in model animals when directly injected in the brain, but it is blocked at the blood-brain barrier (BBB) when peripherally administered and cannot bind to its brain receptors. Therefore, small compounds that penetrate the BBB and mimic the function of orexin are desirable as therapeutic agents.
Researchers in the International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, have been trying to develop compounds that promote wakefulness and remedies narcolepsy, and they succeeded in synthesizing YNT-185, a non-peptide, selective and potent agonist for the orexin type-2 receptor. In the current study, a research group led by Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Hiromu Tominaga and Masashi Yanagisawa, further examined the pharmacological effect of YNT-185, and verified that peripherally administered YNT-185 penetrates BBB and significantly induces wakefulness, as well as ameliorates narcoleptic symptoms in mouse models. No desensitization was observed after repeated administrations. They also found that daily administrations of YNT-185 prevented increase in the body weight; indeed, narcoleptic patients (and mice) tend to be obese. Their findings provide a proof-of-concept for the treatment of narcolepsy.
Furthermore, the administration of YNT-185 also promotes wakefulness in normal mice without any immediate sleep rebounds. “This compound might also be useful in the treatment of the excessive sleepiness caused by other causes, such as depression, side effects of drugs, jet lag and shift work,” said Yanagisawa. “Additionally, it might be effective in preventing the metabolic syndrome.” They are now trying to refine YNT-185 to further improve potency and bioavailability. A miracle drug for narcolepsy and other sleep disorders may be born in the near future.
Source: Masataka Sasabe – University of Tsukuba
Image Source: NeuroscienceNews.com image is credited to University of Tsukuba.
Original Research: Abstract for “Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models” by Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Hiromu Tominaga, Yukiko Ishikawa, Naoto Hosokawa, Shinobu Ambai, Yuki Kawabe, Shuntaro Uchida, Ryo Nakajima, Tsuyoshi Saitoh, Takeshi Kanda, Kaspar Vogt, Takeshi Sakurai, Hiroshi Nagase, and Masashi Yanagisawa in PNAS. Published online May 15 2017 doi:10.1073/pnas.1700499114
[cbtabs][cbtab title=”MLA”]University of Tsukuba “Wake Prompting Compound Validated.” NeuroscienceNews. NeuroscienceNews, 30 May 2017.
<https://neurosciencenews.com/orexin-a-narcolepsy-6799/>.[/cbtab][cbtab title=”APA”]University of Tsukuba (2017, May 30). Wake Prompting Compound Validated. NeuroscienceNew. Retrieved May 30, 2017 from https://neurosciencenews.com/orexin-a-narcolepsy-6799/[/cbtab][cbtab title=”Chicago”]University of Tsukuba “Wake Prompting Compound Validated.” https://neurosciencenews.com/orexin-a-narcolepsy-6799/ (accessed May 30, 2017).[/cbtab][/cbtabs]
Abstract
Dissociable Roles of Cerebral μ-Opioid and Type 2 Dopamine ReceptorProgressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS
Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.
“Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models” by Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Hiromu Tominaga, Yukiko Ishikawa, Naoto Hosokawa, Shinobu Ambai, Yuki Kawabe, Shuntaro Uchida, Ryo Nakajima, Tsuyoshi Saitoh, Takeshi Kanda, Kaspar Vogt, Takeshi Sakurai, Hiroshi Nagase, and Masashi Yanagisawa in PNAS. Published online May 15 2017 doi:10.1073/pnas.1700499114
