Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models
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, nonpe...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2017-05, Vol.114 (22), p.5731-5736 |
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| creator | Irukayama-Tomobe, Yoko Ogawa, Yasuhiro Tominaga, Hiromu Ishikawa, Yukiko Hosokawa, Naoto Ambai, Shinobu Kawabe, Yuki Uchida, Shuntaro Nakajima, Ryo Saitoh, Tsuyoshi Kanda, Takeshi Vogt, Kaspar Sakurai, Takeshi Nagase, Hiroshi Yanagisawa, Masashi |
| description | 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-ablatedmice, 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. |
| doi_str_mv | 10.1073/pnas.1700499114 |
| format | Article |
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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-ablatedmice, 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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1700499114</identifier><identifier>PMID: 28507129</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Aniline Compounds - chemistry ; Aniline Compounds - pharmacology ; Animal models ; Animals ; Benzamides - chemistry ; Benzamides - pharmacology ; Biological Sciences ; Body temperature ; Brain ; Brain slice preparation ; Cataplexy ; Cataplexy - drug therapy ; Cells ; Desensitization ; Disease Models, Animal ; Hypothalamus ; Hypothalamus - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Narcolepsy ; Narcolepsy - drug therapy ; Neurons ; Orexin Receptors - agonists ; Orexin Receptors - genetics ; Orexins ; Orexins - genetics ; Orexins - metabolism ; Patch-Clamp Techniques ; Peptides ; Pharmacology ; Rodents ; Sleep ; Sleep - drug effects ; Sleep and wakefulness ; Sleep disorders ; Sleep Disorders, Circadian Rhythm - drug therapy ; Wakefulness ; Wakefulness - drug effects ; Wakefulness-Promoting Agents - therapeutic use</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2017-05, Vol.114 (22), p.5731-5736</ispartof><rights>Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences May 30, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-71d483e5a94d70cc35a3de98b4b8297bd31fe859b2c13990699046c63592f9cb3</citedby><cites>FETCH-LOGICAL-c509t-71d483e5a94d70cc35a3de98b4b8297bd31fe859b2c13990699046c63592f9cb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26483380$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26483380$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28507129$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Irukayama-Tomobe, Yoko</creatorcontrib><creatorcontrib>Ogawa, Yasuhiro</creatorcontrib><creatorcontrib>Tominaga, Hiromu</creatorcontrib><creatorcontrib>Ishikawa, Yukiko</creatorcontrib><creatorcontrib>Hosokawa, Naoto</creatorcontrib><creatorcontrib>Ambai, Shinobu</creatorcontrib><creatorcontrib>Kawabe, Yuki</creatorcontrib><creatorcontrib>Uchida, Shuntaro</creatorcontrib><creatorcontrib>Nakajima, Ryo</creatorcontrib><creatorcontrib>Saitoh, Tsuyoshi</creatorcontrib><creatorcontrib>Kanda, Takeshi</creatorcontrib><creatorcontrib>Vogt, Kaspar</creatorcontrib><creatorcontrib>Sakurai, Takeshi</creatorcontrib><creatorcontrib>Nagase, Hiroshi</creatorcontrib><creatorcontrib>Yanagisawa, Masashi</creatorcontrib><title>Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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-ablatedmice, 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.</description><subject>Aniline Compounds - chemistry</subject><subject>Aniline Compounds - pharmacology</subject><subject>Animal models</subject><subject>Animals</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Biological Sciences</subject><subject>Body temperature</subject><subject>Brain</subject><subject>Brain slice preparation</subject><subject>Cataplexy</subject><subject>Cataplexy - drug therapy</subject><subject>Cells</subject><subject>Desensitization</subject><subject>Disease Models, Animal</subject><subject>Hypothalamus</subject><subject>Hypothalamus - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Narcolepsy</subject><subject>Narcolepsy - drug therapy</subject><subject>Neurons</subject><subject>Orexin Receptors - agonists</subject><subject>Orexin Receptors - genetics</subject><subject>Orexins</subject><subject>Orexins - genetics</subject><subject>Orexins - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Peptides</subject><subject>Pharmacology</subject><subject>Rodents</subject><subject>Sleep</subject><subject>Sleep - drug effects</subject><subject>Sleep and wakefulness</subject><subject>Sleep disorders</subject><subject>Sleep Disorders, Circadian Rhythm - drug therapy</subject><subject>Wakefulness</subject><subject>Wakefulness - drug effects</subject><subject>Wakefulness-Promoting Agents - therapeutic use</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxS1ERZfCmRMoEhcuacdfieeChCq-pKq9lLPlOLMlq8QOdrZq_ntcbWmBg8eS5zdPfvMYe8PhlEMrz-bg8ilvARQi5-oZ23BAXjcK4TnbAIi2NkqoY_Yy5x0AoDbwgh0Lo6HlAjfMX8Yw07wMPVUx0d0QqmWdqRZVIl_eY6rcTQxDXio30TjE5BbKVXDJx5HmvNbeLW4e6W6t8jqVgSlXRWSK-0yl9jTmV-xo68ZMrx_uE_bjy-fr82_1xdXX7-efLmqvAZe65b0ykrRD1bfgvdRO9oSmU50R2Ha95FsyGjvhuUSEphzV-EZqFFv0nTxhHw-6876bqPcUluRGO6dhcmm10Q32304YftqbeGu1aoqGKAIfHgRS_LWnvNhpyJ7G0QUqfiw3iAqU0bKg7_9Dd3GfQrFnOSrdNiCBF-rsQPkUc060ffwMB3sfoL0P0D4FWCbe_e3hkf-TWAHeHoBdLuE89ZuyO2lA_gZe7KLl</recordid><startdate>20170530</startdate><enddate>20170530</enddate><creator>Irukayama-Tomobe, Yoko</creator><creator>Ogawa, Yasuhiro</creator><creator>Tominaga, Hiromu</creator><creator>Ishikawa, Yukiko</creator><creator>Hosokawa, Naoto</creator><creator>Ambai, Shinobu</creator><creator>Kawabe, Yuki</creator><creator>Uchida, Shuntaro</creator><creator>Nakajima, Ryo</creator><creator>Saitoh, Tsuyoshi</creator><creator>Kanda, Takeshi</creator><creator>Vogt, Kaspar</creator><creator>Sakurai, Takeshi</creator><creator>Nagase, Hiroshi</creator><creator>Yanagisawa, Masashi</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170530</creationdate><title>Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models</title><author>Irukayama-Tomobe, Yoko ; Ogawa, Yasuhiro ; Tominaga, Hiromu ; Ishikawa, Yukiko ; Hosokawa, Naoto ; Ambai, Shinobu ; Kawabe, Yuki ; Uchida, Shuntaro ; Nakajima, Ryo ; Saitoh, Tsuyoshi ; Kanda, Takeshi ; Vogt, Kaspar ; Sakurai, Takeshi ; Nagase, Hiroshi ; Yanagisawa, Masashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-71d483e5a94d70cc35a3de98b4b8297bd31fe859b2c13990699046c63592f9cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Aniline Compounds - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Irukayama-Tomobe, Yoko</au><au>Ogawa, Yasuhiro</au><au>Tominaga, Hiromu</au><au>Ishikawa, Yukiko</au><au>Hosokawa, Naoto</au><au>Ambai, Shinobu</au><au>Kawabe, Yuki</au><au>Uchida, Shuntaro</au><au>Nakajima, Ryo</au><au>Saitoh, Tsuyoshi</au><au>Kanda, Takeshi</au><au>Vogt, Kaspar</au><au>Sakurai, Takeshi</au><au>Nagase, Hiroshi</au><au>Yanagisawa, Masashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2017-05-30</date><risdate>2017</risdate><volume>114</volume><issue>22</issue><spage>5731</spage><epage>5736</epage><pages>5731-5736</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>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-ablatedmice, 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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>28507129</pmid><doi>10.1073/pnas.1700499114</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2017-05, Vol.114 (22), p.5731-5736 |
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| subjects | Aniline Compounds - chemistry Aniline Compounds - pharmacology Animal models Animals Benzamides - chemistry Benzamides - pharmacology Biological Sciences Body temperature Brain Brain slice preparation Cataplexy Cataplexy - drug therapy Cells Desensitization Disease Models, Animal Hypothalamus Hypothalamus - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Narcolepsy Narcolepsy - drug therapy Neurons Orexin Receptors - agonists Orexin Receptors - genetics Orexins Orexins - genetics Orexins - metabolism Patch-Clamp Techniques Peptides Pharmacology Rodents Sleep Sleep - drug effects Sleep and wakefulness Sleep disorders Sleep Disorders, Circadian Rhythm - drug therapy Wakefulness Wakefulness - drug effects Wakefulness-Promoting Agents - therapeutic use |
| title | Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models |
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