Combined M1 Muscarinic/Sigma 1 Receptor Agonist In the early 1990s, a pivotal study demonstrated that activation of muscarinic cholinergic receptors could modulate the APP processing toward a non-amyloidogenic pathway (Nitsch et al., 1992), thereby reducing the production of toxic Aß. It was later shown that the M1 muscarinic receptors in particular played a key role in modulating the AD-like amyloid pathology in vivo (Caccamo et al., 2006). Following these seminal discoveries, it was hypothesized that M1 receptor agonists could extend the cholinergic-based therapeutic arsenal for AD: they should, not only enhance the cholinergic tone for the cognitive benefits of AD patients, but also provide disease-modifying properties. Unfortunately, first generation muscarinic agonists lacked specificity for the M1 receptors, and activation of other receptor subtypes led to major side effects (Fisher, 2008). However, the generation of novel subtype specific muscarinic agonists has renewed the interest for this type of compounds (Fisher, 2012).
Given the complexity of AD pathophysiology, drugs that can target multiple receptors or impaired signaling pathways would likely offer a therapeutic advantage over more conventional single-target drug, as illustrated in the previous section. In that regards, the novel compound AF710B (aka ANAVEX 3-71) merits further attention. It is a combined selective allosteric M1 muscarinic and sigma 1 receptor agonist (Fisher et al., 2016). Targeting sigma 1 receptor has been shown to provide neuroprotection and anti-amnestic properties (Marrazzo et al., 2005; Maurice and Su, 2009; Villard et al., 2011). Combined with M1 muscarinic receptor-mediated effects on APP metabolism, it would confer AF710B a pharmacological profile of interest to tackle various pathological aspects of AD.
AF710B can rescue synapse loss in vitro, while low doses of the compound can attenuate cognitive deficits and alleviate hallmarks of the established AD-like pathology in 3xTg-AD mice (Fisher et al., 2016). In order to validate the putative disease-modifying effect of the drug, AF710B was administered (in the micromolar range) per os daily to post-plaque McGill-R-Thy1-APP rats for 5 months. Completion of the treatment was followed by a wash-out phase of 5 weeks, a unique experimental design key to discriminate true disease-modifying effects from symptomatic effects. The former should disappear after treatment cessation while the latter would be persistent (Ploeger and Holford, 2009). This treatment regimen was sufficient to fully restore cognition in the McGill tg rats. It also led to a substantial decrease in the production of cortical Aß and in the amount of mature amyloid plaques. Interestingly, the reduction in Aß load was accompanied by an increase in CSF Aß42 levels, suggesting that the drug could not only lower Aß production but also increase its clearance (Hall et al., 2018). Of note, this finding may be of translational value to non-invasively follow treatment response in a human population. Further to it, CNS inflammation was decreased, as mirrored by the abolishment of microglia recruitment toward Aß-burdened neurons in the hippocampus and the normalization of hippocampal Iba1 protein levels and cortical IL-10 mRNA expression levels. Finally, these changes were accompanied by an increase in synaptophysin levels, suggesting possible synaptogenic activity (Hall et al., 2018).
In summary, with M1/sigma-1 activity as well as putative disease-modifying properties at very low dose, AF710B is well positioned for therapeutic interventions in AD. The case of AF710B as detailed above provides interesting clues pertaining to potentially increasing the predictive value of preclinical studies. In this particular case, results from the study in McGill-R-Thy1-APP tg rats complemented the initial findings of AF710B beneficial effects in trihexyphenidyl rats and tg mice, by offering new insights into the properties of the drug (Fisher et al., 2016; Hall et al., 2018). Such approach, where efficacy of a drug is validated in several models and under different conditions, should be encouraged before translation to human trials. This is particularly important considering that no single model can recapitulate all aspects of the human disease.
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