Neuroprotective Effects of Cholinesterase Inhibitors: Current Scenario in Therapies for Alzheimer’s Disease and Future Perspectives

Abstract

Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease conceptualized as a continuous process, ranging from mild cognitive impairment (MCI), to the mild, moderate, and severe clinical stages of AD dementia. AD is considered a complex multifactorial disease. Currently, the use of cholinesterase inhibitors (ChEI), such as tacrine, donepezil, rivastigmine, and galantamine, has been the main treatment for AD patients. Interestingly, there is evidence that ChEI also promotes neuroprotective effects, bringing some benefits to AD patients. The mechanisms by which the ChEI act have been investigated in AD. ChEI can modulate the PI3K/AKT pathway, which is an important signaling cascade that is capable of causing a significant functional impact on neurons by activating cell survival pathways to promote neuroprotective effects. However, there is still a huge challenge in the field of neuroprotection, but in the context of unravelling the details of the PI3K/AKT pathway, a new scenario has emerged for the development of more efficient drugs that act on multiple protein targets. Thus, the mechanisms by which ChEI can promote neuroprotective effects and prospects for the development of new drug candidates for the treatment of AD are discussed in this review.

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease

“…The efficacy of each of them has been extensively studied in several studies, both in animal models and clinical trials. Its use has shown that it has a beneficial effect in all stages of the disease and could also have a neuroprotective effect by increasing cell viability and reducing neuronal death, as well as the presence of inflammatory mediators [ 225 , 226 ].…”

The “Cerebrospinal Fluid Sink Therapeutic Strategy” in Alzheimer’s Disease—From Theory to Design of Applied Systems

“…One major limitation derives from the fact that some therapeutic interventions focus only on one aspect of the disease, such as limiting the neuroinflammation [ 19 ] or modulating the cholinergic system [ 20 ]. Indeed, anticholinergic drugs such as Donepezil and Galantamine are among the first approved and still in-use medications in the daily clinical practice [ 21 ]. Memantine, an N-methyl-D-aspartate (NMDA) receptor blocker, one of the most frequently prescribed medications in the United States, is administered alone or in combination therapy in moderate-to-severe AD patients [ 22 ].…”

2-Mercaptobenzimidazole clubbed hydrazone for Alzheimer’s therapy: In vitro, kinetic, in silico, and in vivo potentials

“…Usually, in the brains of AD patients, the activity of AChE remains unchanged or declines ( Kumar et al, 2018 ; Karthika et al, 2022 ). Currently available synthetic acetylcholinesterase inhibitors, including galanthamine, rivastigmine, donepezil, and tacrine, have been clinically used for AD treatment ( Moreira et al, 2022 ). However, these drugs have therapeutic activity along with side effects such as short duration of biological action, gastrointestinal disturbance, low bioavailability, and hepatotoxicity ( Reza et al, 2018 ).…”