单位：[a]Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA[b]Department of Anesthesiology, Children’s Hospital of Fudan University, Shanghai, China[c]Department of Anesthesiology, People’s Hospital of Beijing Daxing District, Beijing, China[d]Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China临床科室麻醉科麻醉科首都医科大学附属北京友谊医院[e]Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China[f]Eagle Pharmaceuticals, Inc., Woodcliff Lake, NJ, USA
Background/Objective: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice. Methods: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3 x/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished atl 2 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. Results: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. Conclusions: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.
基金：
National Institute of General Medical SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM084979]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [R01AG061447]
第一作者单位：[a]Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA[b]Department of Anesthesiology, Children’s Hospital of Fudan University, Shanghai, China
通讯作者：
通讯机构：[a]Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA[*1]Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, 305 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
推荐引用方式(GB/T 7714)：
Yun Shi,Lei Zhang,Xue Gao,et al.Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice[J].JOURNAL of ALZHEIMERS DISEASE.2020,76(4):1375-1389.doi:10.3233/JAD-200227.
APA：
Yun Shi,Lei Zhang,Xue Gao,Jing Zhang,Matan Ben Abou...&Huafeng Wei.(2020).Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.JOURNAL of ALZHEIMERS DISEASE,76,(4)
MLA：
Yun Shi,et al."Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice".JOURNAL of ALZHEIMERS DISEASE 76..4(2020):1375-1389
