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.

Keywords: Acetylcholinesterase; PI3K/AKT pathway; butyrylcholinesterase; neurodegenerative diseases; neuroprotection.

Fig. 1

Schematic structure of AChE showing the gorge region, active catalytic site (CAS), and the peripheral anionic site (PAS).

Fig. 2

Structures of the traditional ChEI.

Fig. 3

Activities of traditional ChEI on multi-targets in AD may lead to various therapeutic effects, which altogether provide neuroprotection.

Fig. 4

Schematic representation of PI3K/AKT signaling pathway ChEI binding leads to the stimulation of α4 and α7 nicotinic acetylcholine receptors (nAChRs); subsequently, occurs the activation of tyrosine kinase Fyn and Janus-activated kinase 2 (JAK2), leading to the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). PI3K converts phosphatidylinositol (3,4)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which activates protein kinase B (AKT). mTOR Complex 2 (mTORC2) also activate AKT signaling. PI3K/AKT pathway regulates several cellular functions, such as inhibition of Glycogen synthase kinase-3β (GSK-3β) that affects tau hyperphosphorylation, inhibition of Forkhead box O (FOXO) and Bcl-2-associated death promoter (BAD) proteins, which are cell survival regulators, such as B-cell lymphoma 2 (Bcl-2) and Bcl-2, and B-cell lymphoma-extra large (Bcl-xL). AKT also activates the mTOR Complex 1 (mTORc1) autophagy regulator and NRF2, which promotes antioxidant response. In AD, the Aβ also acts by inducing GSK-3β activity, increased NFT formation. The PI3K/AKT signaling pathway can be regulated in several ways. The Phosphatase and tensin homolog (PTEN) protein and Src homology domain-containing inositol 5^′-phosphatase 1 (SHIP1) induce the dephosphorylation of PIP3 into PIP2, being negative regulators of PI3K/AKT signaling. PH domain and leucine-rich repeat protein phosphatase (PHLPP) and protein phosphatase 2A (PP2A) are also downregulators of AKT protein.

Fig. 5

Chemical structure of tacrine and most potent tacrine-based hybrids as ChE inhibitors described in the last years. The color pink highlights the 1,2,3,4-tetrahydroakridin-9-amine rings as derivatives in each structure.

Fig. 6

Donepezil and some of the most potent ChE inhibitors derived from donepezil lately developed. Highlighted in blue are the indanone fragments, in red benzylpiperidines moieties, and in pink the 1,2,3,4-tetrahydroakridin-9-amine rings in each structure.

Fig. 7

Multi-target effects of cholinesterase inhibitors on different pathways involved in the development of Alzheimer’s disease.