Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101
in an Alzheimer’s disease mouse model : A Comparative study with
donepezil
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