Neuropharmacology of Cevimeline and Muscarinic Drugs—Focus on Cognition and Neurodegeneration

Abstract

At present, Alzheimer’s disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

Clemastine Promotes Differentiation of Oligodendrocyte Progenitor Cells Through the Activation of ERK1/2 via Muscarinic Receptors After Spinal Cord Injury

“…With the binding of these allosteric modulators, the affinity and/or efficacy of orthosteric (ACh) ligands were affected at the same time ( Bock et al, 2018 ). In addition, the cholinergic system can be therapeutically affected by either direct-acting or indirect-acting cholinergic agents ( Oleksak et al, 2021 ). However, generating ligands with a high degree of selectivity at each muscarinic receptor subtype has been exceptionally challenging ( Thomsen et al, 2018 ).…”

“…It has been reported that clemastine is a MR antagonist, possibly possessing higher affinity toward the M1/M3 receptor than other receptor subtypes ( Kubo et al, 1987 ); in further analyses, the target receptor(s) of clemastine was identified in the OPC culture from M1R–M5R knockout mice and then, the effects of the anti-muscarinic compounds were abolished in MR1-knockout mice, inducing similar numbers of OPCs and differentiated OLs compared to the vehicle-treated M1R-knockout mice, possibly suggesting that M1R could be the most potential mediator of the effects of clemastine on oligodendroglia ( Mei et al, 2016 ), and then the role of clemastine in M1R KO rats with SCI was considered to be explored in our future studies. Cevimeline is a parasympathomimetic and direct-acting MR agonist, usually indicated for treating the symptoms of dry mouth in patients with Sjögren’s syndrome and the therapeutic remedy for treating AD ( Oleksak et al, 2021 ). The toxicity of cevimeline in overdose has not been reported in the medical literature, whereas ingesting high doses of cevimeline (e.g., 30 mg/kg, p.…”

“…Endogenous acetylcholine (ACh) acts as a vital neurotransmitter toward muscarinic receptors in the CNS, influencing learning and memory ( Oleksak et al, 2021 ). Considering that the level of endogenous ACh is high enough to activate MRs, the effect of cevimeline in our study blocked on these phenotypes about OPC differentiation following SCI, indicating that endogenous Ach is not maximal possibly at 7 dpi in this study, in proof of the notion that the limitation of the effects of clemastine was induced by MR agonists to MRs. As previous studies have demonstrated, endogenous ACh showed a generalized decrease from 2.5 h until 4 days post-trauma in the center, periphery, and adjacent regions of the homolateral hemisphere in traumatic brain injury at an early period (such as 2.5 h, 1, and 4 days) ( Scremin et al, 2006 ); meanwhile, intraperitoneal administration of cevimeline induces a significant decline of ACh content in the brain ( Ogane et al, 1990 ).…”

“…However, in SCI, it remains largely unknown whether clemastine promotes OPC differentiation via muscarinic receptors. Thus, a potent direct-acting muscarinic receptor agonist cevimeline, same as clemastine, which could cross the blood–brain barrier ( Oleksak et al, 2021 ), was chosen in this study to disturb the effect of clemastine via MRs for exploring the underlying mechanism of clemastine in SCI.…”

Synthetic Routes to Approved Drugs Containing a Spirocycle

“…Originated from Israel Institute of Biological Research, the drug was developed by Daiichi Sankyo company and gained regulatory approval in 2000 for the treatment of dry mouth and Sjögren's syndrome [62]. Recently, the drug has been investigated on such therapeutic areas as cognitive impairment and neurodegenerative diseases [63].…”