4.7 Article

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

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NEUROPHARMACOLOGY
卷 242, 期 -, 页码 -

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PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2023.109733

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

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This study explores the potential of combining FENM and S1R agonists in the treatment of Alzheimer's disease. The results showed that most FENM-based combinations can protect against learning deficits caused by A beta 25-35, with better efficacy in short-term memory.
Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the A beta 25-35 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 path-ways, have been suggested to more adequately address neuroprotection. As several agonists of the sigma-1 re-ceptor (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 Mem-antine. A beta 25-35-treated mice were treated with S1R agonists (PRE-084, Igmesine, Cutamesine) and/or FENM, or Memantine, during 7 days after intracerebroventricular administration of oligomerized A beta 25-35. 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 A beta 25-35-induced learning deficits, for both long-and short-term memory responses, with a higher efficiency on the latter. Memantine led to synergistic combi-nation 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.

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