Abstract:
BACKGROUND: Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-beta[25-35] peptide (Abeta(25-35))-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, Abeta(25-35)-injected mice and the transgenic APP(swe)/PSEN1( partial differentialE9) (APP/PS1) line. METHODS: In Abeta(25-35)-treated mice, FENM was infused at 0.03-0.3 mg/kg/day during one week after Abeta(25-35) 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 Abeta(25-35)-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 Abeta(25-35) 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 Abeta(25-35)-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored Abeta(25-35)-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 Abeta(1-40)/Abeta(1-42) and hippocampal LTP alteration. CONCLUSION: These data confirmed the neuroprotective potential of FENM in the pharmacological Abeta(25-35) and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically.

Abstract:
Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the Abeta(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 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. Abeta(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 Abeta(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 Abeta(25-35)-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.