Development of a animal model of acute encephalopathy and an antibody therapy

• Project/Area Number: 26670500
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Okayama University (2015-2016); Kyoto University (2014)
• Principal Investigator: Ohmori Iori 岡山大学, 教育学研究科, 教授 (20403488)
• Co-Investigator(Kenkyū-buntansha): 真下 知士 大阪大学, 医学系研究科, 准教授 (80397554) ; 大内田 守 岡山大学, 医歯薬学総合研究科, 准教授 (80213635)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 急性脳症 / けいれん重積 / 熱性けいれん / 炎症 / 熱性痙攣

Outline of Final Research Achievements

We tried to establish an animal model of acute encephalopathy with convulsive status epilepticus. We used Scn1a mutant rats because SCN1A mutations have been linked to hyperthermia-induced seizure susceptibility and acute encephalopathy with a prolonged seizure in human. We induced seizures with various conditions or by using drugs with a proinflammatory effect. Seizures are evoked in Scn1a mutant rats, however, they did not last more than 30 minutes which are often observed in acute encephalopathy in human. Various behavioral tests and pathological examinations of the brain were conducted after provoked seizures. They showed no cognitive impairment and motor disturbance. Pathological tests exhibited no brain edema nor inflammation.

Academic Significance and Societal Importance of the Research Achievements

けいれん重積型急性脳症の発症メカニズムは不明な点が多く，死亡する症例や，知的障害や運動障害，てんかんなどの後遺症を併発する症例がある。病態解明と新規治療法の開発研究にはモデル動物の確立が欠かせない。SCN1A遺伝子異常をもつ患者では急性脳症の合併が多いが、Scn1a遺伝子変異を持つラットで種々の条件を付加して、モデル作製に努めたが、合併症を有するモデルにはならなかった。人の患者における遺伝子解析などで修飾遺伝子の同定を進め、複合的な因子を持つ動物がモデルとなり得るのかもしれない。

Research Products

• [Journal Article] Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS (2016)
  • Author(s): Saitoh, M., Kobayashi, K., Ohmori, I., Tanaka, Y., Tanaka, K., Inoue, T., Horino, A., Ohmura, K., Kumakura, A., Takei, Y., Hirabayashi, S., Kajimoto, M., Uchida, T., Yamazaki, S., Shiihara, T., Kumagai, T., Kasai, M., Terashima, H., Kubota, M., Mizuguchi, M.
  • Journal Title: Journal of the Neurological Sciences Volume: 368 Pages: 272-276
  • DOI: 10.1016/j.jns.2016.07.040
  • Peer Reviewed
• [Journal Article] Action potentials contribute to epileptic high-frequency oscillations recorded with electrodes remote from neurons. (2015)
  • Author(s): Kobayashi K, Akiyama T, Ohmori I, Yoshinaga H, Gotman J.
  • Journal Title: Clin Neurophysiol. Volume: 126 Issue: 5 Pages: 873-881
  • DOI: 10.1016/j.clinph.2014.08.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation. (2014)
  • Author(s): Ohmori, I., Kawakami, N., Liu, S., Wang, H., Miyazaki, I., Asanuma, M., Michiue, H., Matsui, H., Mashimo, T. and Ouchida, M.
  • Journal Title: Epilepsia Volume: 55 Issue: 10 Pages: 1558-1567
  • DOI: 10.1111/epi.12750
  • NAID: 120005522498
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Electrophysiological study of hyperthermia-induced seizures in Scn1a mutant rats (2017)
  • Author(s): 大守伊織
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: 静岡県浜松市
  • Year and Date: 2017-03-28
• [Presentation] A screening test for early diagnosis of Dravet syndrome (2014)
  • Author(s): 大守伊織，大内田守
  • Organizer: 第48回日本てんかん学会学術集会
  • Place of Presentation: 日本，東京
  • Year and Date: 2014-10-02 – 2014-10-03
  • Invited
• [Presentation] Molecular biology of SCN1A mutation-related epileptic syndromes (2014)
  • Author(s): 大守伊織
  • Organizer: 第19回韓国てんかんコングレス
  • Place of Presentation: 韓国 ソウル
  • Year and Date: 2014-06-13 – 2014-06-14
  • Invited
• [Remarks] 岡山大学教育学部特別支援教育講座
  • URL: http://www.office.hyogo-u.ac.jp/jgs/member/data/
• [Remarks] 岡山大学教育者総覧
  • URL: http://soran.cc.okayama-u.ac.jp/view?l=ja&u=4f6bb4c422e9a10774506e4da22f6611
• [Patent(Industrial Property Rights)] てんかん波を伴う疾患治療剤 (2015)
  • Inventor(s): 大守伊織，大内田守，改田祐子
  • Industrial Property Rights Holder: 大守伊織，大内田守，改田祐子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-09-03
  • Overseas
• [Patent(Industrial Property Rights)] てんかん波を伴う疾患治療剤 (2015)
  • Inventor(s): 大守伊織，大内田守，改田祐子
  • Industrial Property Rights Holder: 大守伊織，大内田守，改田祐子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-08-04