MMDN, Univ Montpellier, INSERM, EPHE, Montpellier, France; ReST Therapeutics, Montpellier, France.
MMDN, Univ Montpellier, INSERM, EPHE, Montpellier, France.
Neuropharmacology. 2024 Jan 1;242:109733. doi: 10.1016/j.neuropharm.2023.109733. Epub 2023 Oct 14.
Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the Aβ pharmacological mouse model of Alzheimer's disease (AD). As AD is a complex multi-factorial neurodegenerative pathology, combination therapies relying on drugs acting through different pathways, have been suggested to more adequately address neuroprotection. As several agonists of the sigma-1 receptor (S1R), an intracellular chaperone, are presently in phase 2 or 3 clinical trials in neurodegenetrative diseases including AD, we examined the potentialities of S1R drug-based combinations with FENM, or Memantine. Aβ-treated mice were treated with S1R agonists (PRE-084, Igmesine, Cutamesine) and/or FENM, or Memantine, during 7 days after intracerebroventricular administration of oligomerized Aβ. Mice were then tested for spatial short-term memory on day 8 and non-spatial long-term memory on days 9-10, using the spontaneous alternation or passive avoidance tests, respectively. The FENM or Memantine combination with Donepezil, that non-selectively inhibits acetylcholinesterase and activates S1R, was also tested. The efficacy of combinations using maximal non-active or minimal active doses of S1R agonist or FENM was analyzed using calculations of the combination index, based on simple isobologram representation. Data showed that most of the FENM-based combinations led to synergistic protection against Aβ-induced learning deficits, for both long- and short-term memory responses, with a higher efficiency on the latter. Memantine led to synergistic combination in short-term memory but poorly in long-term memory responses, with either PRE-084 or Donepezil. These study showed that drug combinations based on FENM and S1R agonists may lead to highly effective and synergistic protection in AD, particularly on short-term memory.
氟乙基去甲金刚烷胺（FENM）是一种美金刚衍生物，具有抗健忘和神经保护活性，在阿尔茨海默病（AD）的 Aβ 药理学小鼠模型中得到了证实。由于 AD 是一种复杂的多因素神经退行性病变，因此依赖于通过不同途径发挥作用的药物的联合治疗已被建议更充分地解决神经保护问题。由于几种 sigma-1 受体（S1R）的激动剂，一种细胞内伴侣，目前正在包括 AD 在内的神经退行性疾病的 2 期或 3 期临床试验中，我们研究了 S1R 药物联合 FENM 或美金刚的潜力。在 Aβ 寡聚体脑室内给药后 7 天内，用 S1R 激动剂（PRE-084、Igmesine、Cutamesine）和/或 FENM 或美金刚治疗 Aβ 处理的小鼠。然后，使用自发交替或被动回避测试，分别在第 8 天测试小鼠的空间短期记忆和第 9-10 天测试非空间长期记忆。还测试了与多奈哌齐联合使用的 FENM 或美金刚组合，该药物非选择性抑制乙酰胆碱酯酶并激活 S1R。使用基于简单等剂量图表示的组合指数计算，分析了使用 S1R 激动剂或 FENM 的最大非活性或最小活性剂量的组合的疗效。数据表明，大多数基于 FENM 的组合对 Aβ 诱导的学习缺陷有协同保护作用，无论是长时记忆还是短时记忆反应，后者的效率更高。美金刚在短期记忆中产生协同组合，但在长期记忆反应中效果不佳，无论是 PRE-084 还是多奈哌齐。这些研究表明，基于 FENM 和 S1R 激动剂的药物联合可能会导致 AD 中非常有效和协同的保护作用，特别是在短期记忆方面。
