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.