Impaired Cognitive Function Following Chronic Diazepam Treatment in Middle-Aged Mice

• Project/Area Number: 19K18234
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Hirosaki University
• Principal Investigator: Furukawa Tomonori 弘前大学, 医学研究科, 助教 (60402369)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: ベンゾジアゼピン / ジアゼパム / 認知機能 / 海馬LTP / 運動 / 抗不安薬 / 麻酔薬 / 神経棘突起 / 運動負荷 / benzodiazepine / diazepam / Lcn2 / Aged / exercise

Outline of Research at the Start

抗不安薬や睡眠誘導薬として広く使用されるベンゾジアゼピン（BZ）系薬剤は、長期的使用による高齢者の認知症発症リスクの増加が懸念されている。しかし、その弊害がどのようなメカニズムで生じるかは未解明である。本研究では、BZ系薬剤の慢性投与により発現増加するLcn2が認知機能低下に関わると仮説を立て、BZ系薬剤慢性投与によるLcn2の発現調節機構およびLcn2による神経回路機能低下機構を明らかにする。

Outline of Final Research Achievements

It has been reported that long-term benzodiazepine administration induces cognitive decline in older adults, which provides evidence for toxicity. In this study, we investigated the mechanism of cognitive decline due to long-term use of diazepam, a benzodiazepine, and the preventive effect of exercise for the adverse effect of diazepam. In hippocampal region of chronically diazepam administered middle-aged mice, we analyzed apoptosis, neurogenesis, morphological changes in pyramidal neurons and neural circuit function. There were no effects of chronic diazepam on cell death or neurogenesis, but spine density of pyramidal neurons was decreased and long-term potentiation of CA1 and CA3 were attenuated by both diazepam administration and aging. Furthermore, it was found that the adverse effects of diazepam can be prevented by long-term exercise by force-running wheel.

Academic Significance and Societal Importance of the Research Achievements

本研究結果は、長期的なジアゼパム使用によって生じる認知機能低下が海馬領域における神経細胞の新生や細胞死ではなく、形態的特徴の変化による機能的減退によって引き起こされることを示唆するものであり、ジアゼパムの中枢神経系における詳細な分子的作用機序解明への発展が期待できる。運動による認知機能向上は以前から注目されており、近年、末梢血中の運動由来分子が同定され、詳細な研究が期待されている。本研究成果は、運動由来分子の中枢における機能的特性の解明に貢献できると考えられる。運動由来分子の機能的特性が明らかになれば、ジアゼパム等による認知機能減退の予防法や治療法への発展が期待できる。

Research Products

• [Journal Article] The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats (2022)
  • Author(s): Nikaido Yoshikazu、Midorikawa Yoko、Furukawa Tomonori、Shimoyama Shuji、Takekawa Daiki、Kitayama Masato、Ueno Shinya、Kushikata Tetsuya、Hirota Kazuyoshi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-021-03981-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice (2021)
  • Author(s): Furukawa Tomonori、Nikaido Yoshikazu、Shimoyama Shuji、Masuyama Nozomu、Notoya Ayaka、Ueno Shinya
  • Journal Title: Frontiers in Aging Neuroscience Volume: 13 Pages: 777404-777404
  • DOI: 10.3389/fnagi.2021.777404
  • Peer Reviewed / Open Access
• [Journal Article] GABAA receptors and maternally derived taurine regulate the temporal specification of progenitors of excitatory glutamatergic neurons in the mouse developing cortex. (2021)
  • Author(s): Tochitani S, Furukawa T, Bando R, Kondo S, Ito T, Matsushima Y, Kojima T, Matsuzaki H, Fukuda A.
  • Journal Title: Cerebral Cortex Volume: In press Pages: 4554-4575
  • DOI: 10.1093/cercor/bhab106
  • Peer Reviewed / Open Access
• [Journal Article] Copy number variations in Japanese children with autism spectrum disorder (2021)
  • Author(s): Sakamoto, Yui; Shimoyama, Shuji; Furukawa, Tomonori; Adachi, Masaki; Takahashi, Michio; Mikami, Tamaki; Kuribayashi, Michito; Osato, Ayako; Tsushima, Daiki; Saito, Manabu; Ueno, Shinya; Nakamura, Kazuhiko
  • Journal Title: Psychiatric Genetics Volume: - Issue: 3 Pages: 276-276
  • DOI: 10.1097/ypg.0000000000000276
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lipopolysaccharide induces mouse translocator protein (18 kDa) expression via the AP-1 complex in the microglial cell line, BV-2 (2019)
  • Author(s): Shimoyama Shuji、Furukawa Tomonori、Ogata Yoshiki、Nikaido Yoshikazu、Koga Kohei、Sakamoto Yui、Ueno Shinya、Nakamura Kazuhiko
  • Journal Title: PLOS ONE Volume: 14 Issue: 9 Pages: 1-15
  • DOI: 10.1371/journal.pone.0222861
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice (2019)
  • Author(s): Furukawa Tomonori、Nikaido Yoshikazu、Shimoyama Shuji、Ogata Yoshiki、Kushikata Tetsuya、Hirota Kazuyoshi、Kanematsu Takashi、Hirata Masato、Ueno Shinya
  • Journal Title: Journal of Anesthesia Volume: 33 Issue: 4 Pages: 531-542
  • DOI: 10.1007/s00540-019-02663-z
  • NAID: 40021971791
  • Peer Reviewed / Open Access
• [Presentation] ジアゼパム長期使用による海馬神経機能への影響 (2021)
  • Author(s): 増山望、古川智範、二階堂義和、下山修司、能登谷綾香、上野伸哉
  • Organizer: 東北談話会
• [Presentation] GABAA受容体の細胞内分布におけるβ3サブユニットのリン酸化の影響 (2021)
  • Author(s): 藤井萌加、下山修司、古川智範、上野伸哉
  • Organizer: 東北談話会
• [Presentation] The effect of chronic diazepam administration on cognitive function in aged mice. (2020)
  • Author(s): Furukawa Tomonori, Nikaido Yoshikazu, Shimoyama Shuji, Ogata Yoshiki, Ueno Shinya
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] 抗不安薬ジアゼパムの長期使用による海馬神経機能への影響 (2020)
  • Author(s): 古川 智範、二階堂 義和、下山 修司、上野 伸哉
  • Organizer: 第47回日本脳科学会
• [Presentation] The effect of chronic diazepam administration on hippocampus of aged mice. (2020)
  • Author(s): Furukawa Tomonori, Nikaido Yoshikazu, Shimoyama Shuji, Ueno Shinya
  • Organizer: the 98th Annual Meeting of The Physiological Society of Japan
• [Presentation] Chronic diazepam administration impaired hippocampal CA3 LTP and spine morphology in aged mice (2020)
  • Author(s): Furukawa Tomonori, Nikaido Yoshikazu, Shuji Shimoyama, Ogata Yohiski, Ueno Shinya
  • Organizer: 第97回日本生理学会大会
• [Presentation] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice (2019)
  • Author(s): Furukawa Tomonori, Nikaido Yoshikazu, Ogata Yohiski, Kushikata Tetsuya, Hirota Kazuhoshi, Kanematsu Takashi, Hirata Masato, Ueno Shinya
  • Organizer: Hirosaki Medical Forum