Clinical significance
Chronic treatment with I2-IR ligands would constitute a relevant
therapeutic disease-modifying strategy against AD.
INTRODUCTION
Alzheimer’s disease (AD) is the leading cause of dementia among the
elderly and the most common irreversible and uncurable neurodegenerative
disorder, clinically characterised by progressive behavioural
disturbances and memory loss (Murray et al., 2011).Amyloid
β (Aβ) plaques and neurofibrillary tangles consisting of
hyperphosphorylated Tau (p-Tau) are two major neuropathological AD
hallmarks, which lead to synaptic failure (Walsh and Selkoe, 2004;
Selkoe, 2008; DeTure and Dickson, 2019). Moreover, the inflammatory
response triggered by Aβ deposits and Tau hyperphosphorylation, among
others and mediated by activated microglia and reactive astrocytes has a
key role in the progression of AD. (Dickson and Rogers, 1992; MERAZ RIOS
et al., 2013). Thus, targeting Aβ aggregation, p-Tau, and
neuroinflammation has been proved so far, the main disease-modifying
strategy for treating AD.
However, up to date, only symptomatic treatments, including theacetylcholinesteraseinhibitors (AChEI) and the N-methyl-D-aspartatereceptorantagonists are available for AD therapy. Those drugs showed modest
symptomatic benefits on behaviour and cognition but they did not halt
its progression(Grossberg, 2003; Mehta et al., 2012). Among AChEI,
donepezil is clinically used for cognitive dysfunction in AD (Giacobini,
2000). Besides its main effects related to the enhancement of
cholinergic transmission, donepezil has been demonstrated to exert the
potential for disease pathway modifications in AD, including attenuation
of Aβ load and anti-inflammatory properties in vitro and in
vivo (Kim et al., 2014). However, at a clinical level, it lacks a
curative effect, thereby the identification of new molecular targets for
the development of treatments is crucial. In this context, to further
enhance the non-cholinergic therapeutic effects of donepezil, a
combination of donepezil with other neuroprotective agents could provide
a novel approach to preserve the cognitive function and/or delay AD
pathology.
I2 imidazoline receptors (I2-IR) are receiving growing attention due to
the neuroprotective effects in the central nervous system (CNS)
(Bousquet et al., 2020). In the brain, I2-IR are found in both neurons
and glial cells (Regunathan et al., 1993; Olmos et al., 1994), and their
modulation has been associated with neurodegenerative disorders,
including AD (Ruiz et al., 1993). Most notably, the density of I2-IR was
found increased in AD patients (Garcia-Sevilla et al., 1998). Several
lines of evidence provided by our group demonstrated that selective
I2-IR ligands protected against cognitive impairment ameliorating AD
pathological features related to APP processing, Tau
hyperphosphorylation, neuroinflammation and oxidative stress (OS)
processes, using well- established AD animal models (Abás et al., 2017;
Griñán-Ferré et al., 2019; Abás et al., 2020; Vasilopoulou et al.,
2020b). Likewise,agmatine,
the proposed endogenous ligand for I2-IR, prevented cognitive deficits
in Aβ 1-42 peptide injected mice and of note its effect was augmented
and attenuated by I2-IR agonists and antagonists respectively (Kotagale
et al., 2020). Collectively, this evidence supports the potential
therapeutic effect of I2-IR ligands in AD.
Among the I2-IR ligands, the selective I2-IR ligand LSL60101
[2-(2-benzofuranyl)imidazole)] (Ki ratio for
α2/I2-receptors=286) has been associated with the
induction of several central effects, such as acute hyperphagic effects
(Menargues et al., 1994), inhibition of the development of
opioid-induced tolerance and potentiation of morphine analgesia (Boronat
et al., 1998). Interestingly, LSL60101 was shown to promote neuronal
protection mediated by the induction of reactive astrocytes (Casanovas
et al., 2000). However, the neuroprotective effect of LSL60101 on AD
pathological conditions has not been reported.
In the present in vivo study, we explored the I2-IR ligand
LSL60101 beneficial effects on the behavioural capabilities and
cognitive impairments presented in AD, as well as on AD hallmarks,
including neuroinflammation, glial reactivity and synaptic plasticity by
using the 5XFAD mouse model, a widely accepted transgenic mouse model
for early-onset AD. Additionally, the comparative effect withdonepezil,
considered a symptomatic AD treatment, was investigated alone and in
combination therapy with the I2-IR ligand LSL60101 to decipher joint
effects of both compounds in ameliorating AD pathology and molecular
changes presented by 5XFAD mice.