Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice
| Autor: | Jing Zhang, Yun Shi, Matan Ben Abou, Qingcheng Meng, Adrian Hepner, Lei Zhang, Xue Gao, Maryellen F. Eckenhoff, Ge Liang, Huafeng Wei |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug Amyloid media_common.quotation_subject Morris water navigation task Pharmacology Dantrolene intranasal administration 03 medical and health sciences Amyloid beta-Protein Precursor Mice 0302 clinical medicine cognitive dysfunction Alzheimer Disease Memory medicine Animals Fear conditioning Administration Intranasal media_common Memory Disorders business.industry General Neuroscience Therapeutic effect Brain General Medicine Psychiatry and Mental health Clinical Psychology Disease Models Animal 030104 developmental biology Neuroprotective Agents Immunohistochemistry Nasal administration Geriatrics and Gerontology business Alzheimer’s disease 030217 neurology & neurosurgery medicine.drug Research Article |
| Zdroj: | Journal of Alzheimer's Disease |
| ISSN: | 1875-8908 1387-2877 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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