Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease
Abstract Background Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-β[25–35] peptide (Aβ25–35)-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 t...
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BMC
2025-01-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-024-01648-9 |
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| author | Allison Carles Aline Freyssin Sarra Guehairia Thomas Reguero Michel Vignes Hélène Hirbec Gilles Rubinstenn Tangui Maurice |
| author_facet | Allison Carles Aline Freyssin Sarra Guehairia Thomas Reguero Michel Vignes Hélène Hirbec Gilles Rubinstenn Tangui Maurice |
| author_sort | Allison Carles |
| collection | DOAJ |
| description | Abstract Background Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-β[25–35] peptide (Aβ25–35)-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, Aβ25–35-injected mice and the transgenic APPswe/PSEN1∂E9 (APP/PS1) line. Methods In Aβ25–35-treated mice, FENM was infused at 0.03–0.3 mg/kg/day during one week after Aβ25–35 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 Aβ25–35-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 Aβ25–35 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 Aβ25–35-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored Aβ25–35-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 Aβ1-40/Aβ1-42 and hippocampal LTP alteration. Conclusion These data confirmed the neuroprotective potential of FENM in the pharmacological Aβ25–35 and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically. |
| format | Article |
| id | doaj-art-04b5df48fd14463fb6f33f575da0c973 |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-04b5df48fd14463fb6f33f575da0c9732025-01-12T12:10:57ZengBMCAlzheimer’s Research & Therapy1758-91932025-01-0117112210.1186/s13195-024-01648-9Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's diseaseAllison Carles0Aline Freyssin1Sarra Guehairia2Thomas Reguero3Michel Vignes4Hélène Hirbec5Gilles Rubinstenn6Tangui Maurice7MMDN, Univ Montpellier, EPHE, INSERMMMDN, Univ Montpellier, EPHE, INSERMMMDN, Univ Montpellier, EPHE, INSERMMMDN, Univ Montpellier, EPHE, INSERMIBMM, Univ Montpellier, CNRS, ENSCMIGF, Univ Montpellier, CNRS, INSERMReST TherapeuticsMMDN, Univ Montpellier, EPHE, INSERMAbstract Background Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-β[25–35] peptide (Aβ25–35)-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, Aβ25–35-injected mice and the transgenic APPswe/PSEN1∂E9 (APP/PS1) line. Methods In Aβ25–35-treated mice, FENM was infused at 0.03–0.3 mg/kg/day during one week after Aβ25–35 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 Aβ25–35-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 Aβ25–35 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 Aβ25–35-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored Aβ25–35-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 Aβ1-40/Aβ1-42 and hippocampal LTP alteration. Conclusion These data confirmed the neuroprotective potential of FENM in the pharmacological Aβ25–35 and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically.https://doi.org/10.1186/s13195-024-01648-9Fluoroethylnormemantine (FENM)Alzheimer's diseaseDrug infusionNeuroprotectionNMDA receptor expression |
| spellingShingle | Allison Carles Aline Freyssin Sarra Guehairia Thomas Reguero Michel Vignes Hélène Hirbec Gilles Rubinstenn Tangui Maurice Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease Alzheimer’s Research & Therapy Fluoroethylnormemantine (FENM) Alzheimer's disease Drug infusion Neuroprotection NMDA receptor expression |
| title | Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease |
| title_full | Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease |
| title_fullStr | Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease |
| title_full_unstemmed | Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease |
| title_short | Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease |
| title_sort | neuroprotection by chronic administration of fluoroethylnormemantine fenm in mouse models of alzheimer s disease |
| topic | Fluoroethylnormemantine (FENM) Alzheimer's disease Drug infusion Neuroprotection NMDA receptor expression |
| url | https://doi.org/10.1186/s13195-024-01648-9 |
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