Fluoroethylnormemantine (FENM) shows synergistic protection in combination with a sigma-1 receptor agonist in a mouse model of Alzheimer's disease

Neuropharmacology. 2024 Jan 1:242:109733. doi: 10.1016/j.neuropharm.2023.109733. Epub 2023 Oct 14.

Abstract

Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the Aβ25-35 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. Aβ25-35-treated mice were treated with S1R agonists (PRE-084, Igmesine, Cutamesine) and/or FENM, or Memantine, during 7 days after intracerebroventricular administration of oligomerized Aβ25-35. 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 Aβ25-35-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.

Keywords: Alzheimer's disease; Fluoroethylnormemantine; NMDA receptor antagonism; Sigma-1 receptor; Therapeutic combinations.

MeSH terms

  • Acetylcholinesterase
  • Alzheimer Disease* / metabolism
  • Animals
  • Donepezil / therapeutic use
  • Memantine / pharmacology
  • Mice
  • Neuroprotective Agents* / pharmacology
  • Neuroprotective Agents* / therapeutic use
  • Receptors, sigma* / metabolism
  • Sigma-1 Receptor

Substances

  • fluoroethylnormemantine
  • Memantine
  • Donepezil
  • Acetylcholinesterase
  • Neuroprotective Agents
  • Receptors, sigma