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Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.
Shi, Yun; Zhang, Lei; Gao, Xue; Zhang, Jing; Ben Abou, Matan; Liang, Ge; Meng, Qingcheng; Hepner, Adrian; Eckenhoff, Maryellen F; Wei, Huafeng.
Afiliación
  • Shi Y; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Zhang L; Department of Anesthesiology, Children's Hospital of Fudan University, Shanghai, China.
  • Gao X; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Zhang J; Department of Anesthesiology, People's Hospital of Beijing Daxing District, Beijing, China.
  • Ben Abou M; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Liang G; Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • Meng Q; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Hepner A; Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
  • Eckenhoff MF; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Wei H; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Alzheimers Dis ; 76(4): 1375-1389, 2020.
Article en En | MEDLINE | ID: mdl-32623395
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×/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 at12 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Dantroleno / Enfermedad de Alzheimer / Memoria Límite: Animals Idioma: En Revista: J Alzheimers Dis Asunto de la revista: GERIATRIA / NEUROLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Dantroleno / Enfermedad de Alzheimer / Memoria Límite: Animals Idioma: En Revista: J Alzheimers Dis Asunto de la revista: GERIATRIA / NEUROLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos