著者

神林 崇 今西 彩 富永 杜絵 石戸 秀明 入鹿山 容子 韓 庫銀 木村 昌由美 近藤 英明

出版者

日本神経治療学会

雑誌

神経治療学 (ISSN:09168443)

巻号頁・発行日

vol.38, no.4, pp.503-507, 2021 (Released:2022-04-28)

参考文献数

7

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Even though we are currently in the midst of pandemic from coronavirus infection, the new influenza (H1N1) epidemic in 2009–2010 was unforgettable. Concurrently with the H1N1, narcolepsy surged in post–affected children in China. In Northern Europe, narcolepsy surged in children after H1N1 vaccination. Although there were many cases of H1N1 in Japan, there was no change in the incidence of narcolepsy because anti–influenza drugs prevented the disease from becoming more severe and the vaccine did not contain an adjuvant. It has recently become clear that the Spanish flu that prevailed about 100 years ago was also H1N1. Economo's encephalitis lethargica, which was prevalent at the same time, is thought to be autoimmune encephalitis rather than H1N1–induced influenza encephalitis. It has been reported that Economo's encephalitis caused damage to the hypothalamus, including the orexin system, resulting in lethargic symptoms.Since the 2010s, the number of patients with neurodevelopmental disorders (ADHD, ASD) has been increasing among the patients who complain of hypersomnolence. Consideration of the course of symptoms revealed that the patient was originally below the threshold of the diagnostic criteria for neurodevelopmental disease, that hypersomnolence occurred from around adolescence, and that the case also met the criteria for neurodevelopmental disease. Although hypersomnolence was not noticeable in early childhood and inattention was the main symptom, the diagnostic criteria were not met. Hypersomnolence, on the other hand, increased from around adolescence, was added, and attention deficit was exacerbated. Therefore, it is considered that there are many cases that satisfy both the diagnosis of ADHD and central hypersomnia. ADHD characteristics such as attention deficit, hyperactivity, and poor impulsivity may be observed in children who have recovered from Economo's encephalitis and are called post–encephalitis behavioral disorders. The pathophysiology of Economo's encephalitis is presumed to be a disorder of the hypothalamus, including the orexin system, but it is possible that the disorder remained even after recovery.We believe that impaired attention, and restlessness caused by the hypersomnolence in neurodevelopmental disorders can be explained by dysfunctions of the orexin system and its arousal system. H1N1 morbidity may trigger neurodevelopmental disorders accompanied by hypersomnolence.

著者

山元 ひかり 入鹿山 容子 石川 有紀子 滑川 由紀子 根本 剛 田中 大夢 高橋 元樹 柳沢 正史

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-SS-05, 2020 (Released:2020-03-18)

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Loss of orexin-producing neurons in the lateral hypothalamus causes the chronic sleep disorder narcolepsy-cataplexy. Narcoleptic humans suffer from two major symptoms, excessive sleepiness and cataplexy in the active phase, and these symptoms in mouse models are manifested as sleep/wakefulness fragmentation and SOREMs (direct transitions from wakefulness to REM sleep), respectively. The neuropeptides orexin-A (OXA) and orexin-B (OXB) act on two receptors orexin type-1 receptor (OX1R) and orexin type-2 receptor (OX2R). Orexin receptor agonists are expected to be of potential value for treating human narcolepsy. Here, to confirm the fundamental strategy aimed at improving narcoleptic symptoms, we examined the association between orexin receptor subtypes and these symptoms by intracerebroventricular (ICV) administration of the OX2R-selective agonist [Ala11, D-Leu15]-OXB in orexin knockout mice. OXA and [Ala11, D-Leu15]-OXB similarly decreased the number of SOREMs. Further, transition frequencies between NREM sleep and wake states in narcoleptic model mice were similarly decreased. We confirmed in vivo that [Ala11, D-Leu15]-OXB did not activate OX1R-expressing LC noradrenergic neurons by Fos staining. Therefore, OX2R-selective agonism is sufficient to ameliorate narcoleptic symptoms, both cataplexy and fragmentation of wakefulness in model mice. Activation of LC noradrenaline neurons expressing OX1R are not essential for suppression of these symptoms.

著者

入鹿山 容子 桜井 武

出版者

筑波大学

雑誌

基盤研究(C)

巻号頁・発行日

2016-04-01

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敗血症は、細菌による感染を発端として、細菌が産生するエンドトキシンなどの毒素が全身に広がり、播種性血管内凝固症候群(DIC)、多臓器不全、ショックなどを引き起こす全身疾患である。重症度に幅があり敗血症、重症敗血症、敗血症性ショックの順で重篤化し、まだ有効な治療法が確立していない。申請者らは敗血症性ショックモデルマウスに神経ペプチドであるオレキシンを末梢投与すると、オレキシンが全身性炎症状態で障害を受けた血液脳関門を通過し、中枢に作用してバイタルサイン(体温と心拍数)を回復することを見出した。神経活動の指標であるFosを用いた免疫組織学的手法による探索の結果、このオレキシンによる体温の回復作用には延髄縫線核セロトニン神経が活性化されることが重要であることがわかった(Ogawa, Irukayama-Tomobe, eLife, 2016)。さらに延髄縫線核にアデノ随伴ウィルス(AAV)ベクターを用いて抑制性(hM4Di)DREADD(Designer Receptors Exclusively Activated by Designer Drugs) を発現させた場合に、オレキシンの体温上昇作用が消失することを確認した。また、オレキシンの生存率の改善効果に伴いカテコールアミンとコルチコステロンが増加し、炎症性サイトカインが減少することを見出した。このことからオレキシンの生存率改善には抗炎症作用も関連しているのではないかと考えられた。敗血症性ショックモデルマウスにオレキシンを持続投与した後、再度Fosを用いた免疫組織学的手法を用いて標的部位の探索を行った。オレキシン持続投与4時間後ではTMN (histaminergic tuberomammillary hypothalamic nucleus)、VTA(ventral tegmental area)が有意に活性化され、22時間後ではNTS(nucleus of solitary tract)が活性化されるということがわかった。