Research for elucidating mechanisms of stress vulnerability as basis of brain dysfunction caused by periodontal disease

• Project/Area Number: 17K11670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Daiichi University, College of Pharmaceutical Sciences (2019); Hiroshima University (2017-2018)
• Principal Investigator: Yamawaki Yosuke 第一薬科大学, 薬学部, 講師 (90584061)
• Co-Investigator(Kenkyū-buntansha): 兼松 隆 九州大学, 歯学研究院, 教授 (10264053)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 歯周病モデル / PgLPS / ミクログリア / 炎症性サイトカイン / NF-κB / 抗うつ薬 / 歯周病 / 炎症 / 神経細胞 / 中枢機能障害 / 歯性感染 / 免疫

Outline of Final Research Achievements

We investigated whether peripheral inflammation caused by periodontal disease spreads to the central nervous system, which causes neuro-inflammation and stress vulnerability, and whether antidepressants suppress them using periodontal disease model mice and cultured cells. As a result, lipopolysaccharide derived from P. gingivaris (PgLPS) caused microglial activation and inflammatory response in the hippocampus. In addition, PgLPS caused neuronal cell death by inducing an inflammatory response by activating the NF-κB pathway via TLR2/4 in microglia. Furthermore, antidepressants suppressed microglia-induced neuronal cell death by inhibiting the NF-κB pathway in microglia. In mice, antidepressants also suppressed hippocampal inflammation and tended to suppress PgLPS-induced depression-like behavior.

Academic Significance and Societal Importance of the Research Achievements

歯周病はP.gingivarisなどの細菌が口腔に感染することで引き起こされる慢性的な局所炎症であるが、この炎症は全身へと波及し、心疾患や糖尿病などの全身疾患のみならず、認知機能障害のリスクファクターであることが明らかとなってきた。本研究は、歯周病への罹患がストレス脆弱性にも関与する可能性とその機序を示し、また既存の抗うつ薬が歯周病による中枢炎症を抑制することを示した。歯周病のリスクを知らしめることで認識を改め、また治療薬の可能性を示したという点で意義があると考える。

Research Products

• [Journal Article] Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress (2020)
  • Author(s): Nozaki Kanako、Ito Hikaru、Ohgidani Masahiro、Yamawaki Yosuke、Sahin Ezgi Hatice、Kitajima Takashi、Katsumata Seishi、Yamawaki Shigeto、Kato Takahiro A.、Aizawa Hidenori
  • Journal Title: Neuropharmacology Volume: 162 Pages: 107835-107835
  • DOI: 10.1016/j.neuropharm.2019.107835
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-inflammatory Effects of miRNA-146a Induced in Adipose and Periodontal Tissues (2020)
  • Author(s): Taiki Sanada, Tomomi Sano, Yusuke Sotomaru, Rehab Alshargabi, Yosuke Yamawaki, Akiko Yamashita, Hiroaki Matsunaga, Misaki Iwashita, Takanori Shinjo, Takashi Kanematsu, Tomoichiro Asano, Fusanori Nishimura
  • Journal Title: Biochem Biophys Rep. Volume: Jul Pages: 100757-100757
  • DOI: 10.1016/j.bbrep.2020.100757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Importance of the Habenula for Avoidance Learning Including Contextual Cues in the Human Brain: A Preliminary fMRI Study (2020)
  • Author(s): Yoshino A, Okamoto Y, Sumiya Y, Okada G,Takamura M, Ichikawa N, Nakano T, Shibasaki C, Aizawa H, Yamawaki Y, Kawakami K, Yokoyama S, Yoshimoto J, Yamawaki S
  • Journal Title: Frontiers in Human Neuroscience Volume: 14 Pages: 165-165
  • DOI: 10.3389/fnhum.2020.00165
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure (2019)
  • Author(s): Kanematsu T, Oue K, Okumura T, Harada K, Yamawaki Y, Asano S, Mizokami A, Irifune M, Hirata M
  • Journal Title: J Oral Biosci Volume: 61(2) Issue: 2 Pages: 65-72
  • DOI: 10.1016/j.job.2019.04.002
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates cytokinesis by protecting phosphatidylinositol 4,5-bisphosphate from metabolism in the cleavage furrow (2019)
  • Author(s): Asano, S., Ikura, Y., Nishimoto, M., Yamawaki, Y., Hamao, K., Kamijo, K., Hirata, M. and Kanematsu, T.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12729-12729
  • DOI: 10.1038/s41598-019-49156-3
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice (2019)
  • Author(s): Yamawaki Yosuke、Shirawachi Satomi、Mizokami Akiko、Nozaki Kanako、Ito Hikaru、Asano Satoshi、Oue Kana、Aizawa Hidenori、Yamawaki Shigeto、Hirata Masato、Kanematsu Takashi
  • Journal Title: Neurochemistry International Volume: 131 Pages: 104563-104563
  • DOI: 10.1016/j.neuint.2019.104563
  • Peer Reviewed / Open Access
• [Journal Article] Immobilization stress induces XBP1 splicing in the mouse brain. (2019)
  • Author(s): Hosoi T, Kimura H, Yamawaki Y, Mori K, Ozawa K
  • Journal Title: Biochem Biophys Res Commun Volume: 508 Issue: 2 Pages: 516-520
  • DOI: 10.1016/j.bbrc.2018.11.167
  • Peer Reviewed
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep. Volume: 26 Issue: 12 Pages: 3221-3230
  • DOI: 10.1016/j.celrep.2019.02.066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 総説 うつ病における手綱核の役割-これまでのヒト脳に関する知見を中心に (2018)
  • Author(s): Yoshino A, Aizawa H, Takamura M, Ichikawa N, Shibasaki C, Yamawaki Y, Sasaoka T, Okamoto Y, Yamawaki S.
  • Journal Title: BRAIN and NERVE Volume: 70 Issue: 9 Pages: 1017-1023
  • DOI: 10.11477/mf.1416201121
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2018-09-01
  • Peer Reviewed
• [Journal Article] Data on the effect of maternal separation coupled with social isolation in a forced swim test and gene expression of glial fibrillary acid protein in the prefrontal cortex of rats (2018)
  • Author(s): Yamawaki Y, Nishida M, Harada K. Akagi H
  • Journal Title: Data in Brief Volume: 18 Pages: 496-500
  • Peer Reviewed / Open Access
• [Journal Article] Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice (2018)
  • Author(s): Yamawaki Y, Yoshioka N, Nozaki K, Ito H, Oda K, Harada K, Shirawachi S, Asano S, Aizawa H, Yamawaki S, Kanematsu T, Akagi H
  • Journal Title: Brain research Volume: 1;1680 Pages: 13-38
  • DOI: 10.1016/j.brainres.2017.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates. (2017)
  • Author(s): Lotan A, Lifschytz T, Wolf G, Keller S, Ben-Ari H, Tatarsky P, Pillar N, Oved K, Sharabany J, Merzel TK, Matsumoto T, Yamawaki Y, Mernick B, Avidan E, Yamawaki S, Weller A, Shomron N, Lerer B.
  • Journal Title: Molecular Psychiatry Volume: - Issue: 2 Pages: 158-175
  • DOI: 10.1007/s10905-018-9665-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling (2017)
  • Author(s): Asano Satoshi、Taniguchi Yuri、Yamawaki Yosuke、Gao Jing、Harada Kae、Takeuchi Hiroshi、Hirata Masato、Kanematsu Takashi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 5408-5408
  • DOI: 10.1038/s41598-017-05908-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Possible involvement of AKT-GSK3β signal-up-regulated MEF2D protein in imipramine-enhanced the expression of astrocytic interleukin-10 under inflammatory state (2019)
  • Author(s): Yamawaki Y., Shirawachi S., Takaishi M., Yamawaki S., Kanematsu T.
  • Organizer: AsCNP2019
  • Int'l Joint Research
• [Presentation] Imipramine enhances the expression of astrocytic interleukin-10 under inflammatory state (2018)
  • Author(s): Yosuke Yamawaki, Satomi Shirawachi, Munechika Takaishi, Shigeto Yamawaki, Takashi Kanematsu
  • Organizer: 8th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] グリア細胞間相互作用におけるイミプラミンの抗炎症効果の検討 (2018)
  • Author(s): 山脇洋輔、高石宗佳、山脇成人、兼松隆
  • Organizer: 第28回日本臨床精神神経薬理学会・第48回日本神経精神薬理学会合同年会
• [Presentation] 歯周病原細菌由来リポ多糖（PgLPS）が惹起する脳内炎症の解析 (2018)
  • Author(s): 曽浩紀，山脇洋輔，谷本幸太郎，兼松隆
  • Organizer: 第102回広島大学歯学会例会
• [Presentation] 炎症誘発性摂餌抑制行動における新規分子の解析 (2018)
  • Author(s): 山脇 洋輔, 兼松 隆
  • Organizer: 日本薬学会 第138年会
• [Presentation] Lipopolysaccharideが誘発する摂食抑制行動におけるPLC-related catalytically inactive proteinの役割 (2017)
  • Author(s): 白輪地 聡美, 山脇 洋輔, 兼松 隆
  • Organizer: 第59回 歯科基礎医学会学術大会,
• [Presentation] Anti-inflammatory effects of antidepressant in glial cells (2017)
  • Author(s): 山脇洋輔、白輪地聡美、高石宗佳、山脇成人、兼松 隆
  • Organizer: 第50回 広島大学歯学会