Carles Allison, Freyssin Aline, Guehairia Sarra, Reguero Thomas, Vignes Michel, Hirbec Hélène, Rubinstenn Gilles, Maurice Tangui
MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.
ReST Therapeutics, Paris, France.
Alzheimers Res Ther. 2025 Jan 6;17(1):7. doi: 10.1186/s13195-024-01648-9.
BACKGROUND: Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-β[25-35] peptide (Aβ)-induced neurotoxicity in mice, a pharmacological model of Alzheimer's disease (AD) with high predictive value for drug discovery. Here, as drug infusion is likely to better reflect drug bioavailability due to the interspecies pharmacokinetics variation, we analyzed the efficacy of FENM after chronic subcutaneous (SC) infusion, in comparison with IP injections in two AD mouse models, Aβ-injected mice and the transgenic APP/PSEN1 (APP/PS1) line. METHODS: In Aβ-treated mice, FENM was infused at 0.03-0.3 mg/kg/day during one week after Aβ injection. For comparison, FENM and MEM were administered IP daily at 0.03-0.3 mg/kg. In 10-month-old APP/PS1 mice, FENM was administered during four weeks by daily IP injections at 0.3 mg/kg or chronic SC infusion at 0.1 mg/kg/day. Memory deficits, spatial working memory and recognition memory, were analysed. Markers of neuroinflammation, apoptosis, oxidative stress, and amyloid burden in APP/PS1 mice, were quantified. Markers of synaptic plasticity such as PSD-95 and GluN2A/B/D subunits expression in hippocampus homogenates or synaptosomes were quantified in Aβ-treated mice and synaptic long-term potentiation (LTP) in hippocampal slices was analysed in APP/PS1 mice. RESULTS: Deficits in spontaneous alternation and object recognition in Aβ mice were prevented by infused FENM at all doses tested. Similar effects were observed with the daily FENM or MEM treatments. Animals infused with 0.1 mg/kg/day FENM showed prevention of Aβ-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored Aβ-induced alterations in synaptosomal PSD-95, GluN2A and P-GluN2B levels. GluN2D levels were unchanged whatever the treatment. In APP/PS1 mice, FENM infused or administered IP alleviated spontaneous alternation deficits, neuroinflammation, increases in Aβ/Aβ and hippocampal LTP alteration. CONCLUSION: These data confirmed the neuroprotective potential of FENM in the pharmacological Aβ and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically.
背景：氟乙基金刚烷胺（FENM）是一种新型美金刚（MEM）衍生物，可预防β淀粉样蛋白[25-35]肽（Aβ）诱导的小鼠神经毒性，这是一种阿尔茨海默病（AD）的药理学模型，对药物发现具有很高的预测价值。由于种间药代动力学差异，药物输注可能更能反映药物的生物利用度，因此，我们分析了慢性皮下（SC）输注FENM的疗效，并与两种AD小鼠模型（Aβ注射小鼠和转基因APP/PSEN1（APP/PS1）品系）腹腔注射给药进行比较。 方法：在Aβ处理的小鼠中，Aβ注射后一周内，FENM以0.03-0.3mg/kg/天的剂量进行输注。作为比较，FENM和MEM以0.03-0.3mg/kg的剂量每日腹腔注射给药。在10月龄的APP/PS1小鼠中，FENM通过每日0.3mg/kg腹腔注射或0.1mg/kg/天的慢性皮下输注给药四周。分析记忆缺陷、空间工作记忆和识别记忆。对APP/PS1小鼠的神经炎症、细胞凋亡、氧化应激和淀粉样蛋白负荷标志物进行定量分析。在Aβ处理的小鼠中，对海马匀浆或突触体中突触后密度蛋白95（PSD-95）和N-甲基-D-天冬氨酸受体2A/B/D亚基表达等突触可塑性标志物进行定量分析，并在APP/PS1小鼠中分析海马切片中的突触长时程增强（LTP）。 结果：在所有测试剂量下，输注FENM均可预防Aβ小鼠的自发交替和物体识别缺陷。每日给予FENM或MEM治疗也观察到类似效果。以0.1mg/kg/天的剂量输注FENM的动物可预防Aβ诱导的神经炎症、氧化应激和细胞凋亡。FENM输注可恢复Aβ诱导的突触体PSD-95、N-甲基-D-天冬氨酸受体2A和磷酸化N-甲基-D-天冬氨酸受体2B水平的改变。无论何种治疗，N-甲基-D-天冬氨酸受体2D水平均无变化。在APP/PS1小鼠中，输注或腹腔注射FENM均可减轻自发交替缺陷、神经炎症、Aβ/Aβ增加和海马LTP改变。 结论：这些数据证实了FENM在AD的药理学Aβ和转基因APP/PS1小鼠模型中的神经保护潜力，优于MEM，并表明该药物可有效进行长期输注。
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