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Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer’s disease mouse model : A Comparative study with donepezil
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  • Fotini Vasilopoulou,
  • Sergio Rodríguez-Arevalo,
  • Andrea Bagán,
  • Carmen Escolano,
  • Christian Griñán-Ferré,
  • Mercè Pallàs
Fotini Vasilopoulou
Universitat de Barcelona Facultat de Farmacia
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Sergio Rodríguez-Arevalo
Universitat de Barcelona Facultat de Farmacia
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Andrea Bagán
Universitat de Barcelona Facultat de Farmacia
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Carmen Escolano
Universitat de Barcelona Facultat de Farmacia
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Christian Griñán-Ferré
Universitat de Barcelona Facultat de Farmacia
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Mercè Pallàs
Universitat de Barcelona Facultat de Farmacia
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Abstract

Background and Purpose: The development of effective therapeutic strategies against Alzheimer’s disease (AD) remains a challenge. I2 Imidazoline receptors (I2-IR) ligands have a neuroprotective role in AD. While co-treatment of acetylcholinesterase inhibitors with neuroprotective agents have shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I2-IR ligand LSL60101, donepezil and their combination in 5XFAD mice. Experimental Approach: 5XFAD female mice were treated with low doses of LSL60101 (1mg/kg/day), donepezil (1mg/kg/day), and donepezil plus LSL60101 (1+1mg/kg/day), during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze and three-chamber tests were employed to evaluate the cognitive and behavioural status of the mice after treatment. The effects of the treatments on AD-like pathology were assessed with immunohistochemistry, Western blot and qPCR. Key results: Chronic low-dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety-like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments decreased Aβ-pathology and Tau hyperphosphorylation, and these alterations were accompanied by decreased microglia marker Iba-1 levels and increased Trem2 gene expression. LSL60601 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60601 treatment significantly increased the levels of the synaptic markers post-density 95 (PSD95) and synaptophysin (SYN). Conclusion and implications: Our results suggest that chronic low dose treatment with selective I2-IR ligands can be an effective treatment for AD and provide insights into combination treatments of symptomatic and disease-modifying drugs

Peer review status:ACCEPTED

17 Dec 2020Submitted to British Journal of Pharmacology
18 Dec 2020Submission Checks Completed
18 Dec 2020Assigned to Editor
19 Dec 2020Reviewer(s) Assigned
15 Jan 2021Review(s) Completed, Editorial Evaluation Pending
18 Jan 2021Editorial Decision: Revise Minor
27 Feb 20211st Revision Received
01 Mar 2021Submission Checks Completed
01 Mar 2021Assigned to Editor
01 Mar 2021Reviewer(s) Assigned
08 Mar 2021Review(s) Completed, Editorial Evaluation Pending
10 Mar 2021Editorial Decision: Revise Minor
28 Mar 20212nd Revision Received
28 Mar 2021Submission Checks Completed
28 Mar 2021Assigned to Editor
29 Mar 2021Editorial Decision: Accept