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.

中文翻译：

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鼻内丹特罗林在Alzheimer 5XFAD小鼠中作为疾病改良药物。

背景/目的：本研究比较了在5XFAD阿尔茨海默氏病（AD）小鼠中鼻腔注射与皮下注射丹特罗的有效性和安全性。方法：将5XFAD和野生型（WT）B6SJLF1 / J小鼠分别经鼻或皮下注射丹特罗（5 mg / kg，3×/ wk）或溶媒治疗。早期（ETG）和晚期（LTG）治疗组分别在2个月或6个月大时开始治疗，两个治疗组都在12个月大时结束。评估行为的嗅觉（埋藏食物测试），运动功能（罗塔罗德）和认知（恐惧条件，莫里斯水迷宫）。检查肝组织学（H和E染色）和功能，突触蛋白以及脑淀粉样蛋白免疫组化。鼻内或皮下给药后，在一个单独的队列中确定血浆和脑中丹特罗的浓度。结果：鼻内丹特罗比皮下给药可达到更高的大脑浓度和更低的血浆浓度。两种方法中的丹特罗给药均显着改善了ETG中海马依赖性和非依赖性记忆，而仅鼻内丹特罗改善了LTG中的认知。Dantrolene治疗对5XFAD小鼠的淀粉样蛋白负荷或突触蛋白无明显变化，并且对死亡率，嗅觉，运动或肝功能无明显副作用。在5XFAD小鼠AD症状发作之前或之后开始时，鼻内丹特罗治疗可显着改善记忆力丧失。结论：与经皮下入路相比，长期鼻内给予丹特罗林对记忆力有治疗作用，即使在AD症状发作后也是如此。