Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases on a global scale. Historically, this pathology has been linked to cholinergic transmission, and despite the scarcity of effective therapies, numerous alternative processes and targets have been proposed as potential avenues for comprehending this complex illness. Nevertheless, the fundamental pathophysiological mechanisms underpinning AD remain largely enigmatic, with a growing body of evidence advocating for the significance of muscarinic receptors in modulating the brain’s capacity to adapt and generate new memories. This review summarizes the current state of the art in the field of muscarinic receptors’ involvement in AD. A specific key factor was the relationship between comorbidity and the emergence of new mechanisms.

Synaptosomes are subcellular components isolated from nerve terminations that can be prepared by homogenizing brain tissue in isotonic sucrose solution followed by appropriate centrifugation. Their preparation technique has a long history since synaptosomes were first isolated from nerve endings and described by Gray and Whittaker in 1962. The preparation of synaptosomes produces presynaptic boutons alone or in combination with fragments of postsynaptic membranes. Interestingly, synaptosomes contain organelles and vesicles that express native channels, receptors, and transporters. At 37 °C, these isolated nerve endings are metabolically active and synthesize and release neurotransmitters. They are actively used to investigate neurotransmission, its actors, and the mechanisms of neurotransmitter release. To date, many functional and non-functional applications of synaptosomes have been documented. Due to their versatility, synaptosomes have been actively used to study neuroinflammatory processes.

In recent years, the inhibition of beta-amyloid (Aβ) aggregation has emerged as a potential strategy for Alzheimer’s disease. KLVFF, a small peptide corresponding to the aminoacidic sequence 16-20 of Aβ, reduces Aβ fibrillation dose dependently. Therefore, the toxic and functional characterization of its brain activity is fundamental for clarifying its potential therapeutic role. Accordingly, we studied the modulatory role of KLVFF on the cholinergic receptors regulating dopamine and noradrenaline release in rat synaptosomes. Nicotinic receptors on dopaminergic nerve terminals in the nucleus acccumbens are inhibited by KLVFF, which closely resembles full-length Aβ1-40. Moreover, KLVFF entrapped in synaptosomes does not modify the nicotinic receptor’s function, suggesting that external binding to the receptor is required for its activity. The cholinergic agent desformylflustrabromine counteracts the KLVFF effect. Remarkably, muscarinic receptors on dopaminergic terminals and nicotinic receptors regulating noradrenaline release in the hippocampus are completely insensitive to KLVFF. Based on our findings, KLVFF mimics Aβ1-40 as a negative modulator of specific nicotinic receptor subtypes affecting dopamine transmission in the rat brain. Therefore, new pharmacological strategies using the anti-aggregative properties of KLVFF need to be evaluated for potential interference with nicotinic receptor-mediated transmission.

Anxiety and anxiety-related disorders are becoming more evident every day, affecting an increasing number of people around the world. Metabolic disorders are often associated with anxiety. Furthermore, anxiety branches into metabolic disorders by playing multiple roles as a cofactor, symptom, and comorbidity. Taken together, these considerations open the possibility of integrating the therapy of metabolic disorders with specific drugs for anxiety control. However, anxiolytic compounds often cause disabling effects in patients. The main goal could be to combine therapeutic protocols with compounds capable of reducing side effects while performing multiple beneficial effects. In this article we propose a group of bioactive ingredients called botanicals as a healthy supplement for the treatment of metabolic disorders related to anxiety.

Ongoing global research actions seek to comprehensively understand the adverse impact of stress and anxiety on the physical and mental health of both human beings and animals. Niaprazine (NIA) is a chemical compound that belongs to the class of piperazine derivatives. This compound has recently gained renewed attention due to its potential therapeutic properties for treating certain conditions such as anxiety. Despite its potential benefits, the behavioral effects of NIA have not been thoroughly investigated. This study aimed to examine NIA’s potential as an anti-anxiety and anti-stress agent. After administering either vehicle or NIA in their drinking water to mice for 14 days, we conducted behavioral analyses using the Marble Burying Test and the Elevated Plus Maze test. NIA-treated mice spend more time in the open arms and bury fewer marbles. Moreover, a stability study confirmed the linear relationship between NIA concentration and its response across concentrations encompassing the NIA mother solution and the NIA solutions administered to mice. Also, a preliminary synaptic toxicity analysis showed no direct damage to cortical nerve endings. Here, we show that NIA can modulate anxiety-related behaviors without significantly impacting exploratory activity or adverse effects. Our work describes new findings that contribute to the research on safer and more tolerable anxiety management options.

Ellagic acid (EA) is a natural compound exerting beneficial effects in mammals, including central neuroprotection. Among the central targets, the noradrenergic pathway has been proposed as a suitable candidate and, in this view, we recently proposed the presynaptic α₂ autoreceptors as possible sites of action of this natural polyphenol. Although attractive, our hypothesis is questioned by the unfavourable pharmacokinetic profile of EA, which limits its access to the central nervous system, making impossible its interaction with these receptors. To substantiating the correlation linking EA treatment and the central noradrenergic pathway, we have now extended the study to Urolithins. These are the principal EA metabolites, which are brought in for EA central effects because of their high systemic bioavailability. To address the point, we employed a multidisciplinary approach, which included computational, "in vitro" and "in vivo" studies. The results from "computational" and "in vitro" experiments revealed that Urolithin A (UroA), but not Urolithin B (UroB) or C (UroC), binds to and activates α2 receptor subtypes. Furthermore, the "in vivo" prolonged administration of formulated microdispersion of EA (EAm) in mice led to a marked desensitization of cortical and hippocampal α₂ autoreceptors, also reducing their density. Notably, central effects were associated to a significant changes in gut microbiome composition, towards a metabotype that would preferentially produce UroA. Based on these observations, we propose UroA as one of the systemic "effectors" of the EAm-induced central noradrenergic adaptation, confirming the role of noradrenaline in mediating the EA-mediated health effects.