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 (1 mg-1 kg-1day-1), donepezil (1 mg-1kg-1 day-1), and donepezil plus
LSL60101 (1+1 mg-1 kg-1day-1), 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.
KEYWORDS: I2 Imidazoline receptors, β-amyloid,
neuroinflammation, synaptic plasticity, donepezil, Alzheimer’s disease