A New Therapeutic Target in Alzheimer's Disease Treatment: Attention to Butyrylcholinesterase

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly, characterised by widespread loss of central cholinergic function. The only symptomatic treatment proven effective to date is the use of cholinesterase (ChE) inhibitors to augment surviving cholinergic activity. ChE inhibitors act on the enzymes that hydrolyse acetylcholine (ACh) following synaptic release. In the healthy brain, acetylcholinesterase (AChE) predominates (80%) and butyrylcholinesterase (BuChE) is considered to play a minor role in regulating brain ACh levels. In the AD brain, BuChE activity rises while AChE activity remains unchanged or declines. Therefore both enzymes are likely to have involvement in regulating ACh levels and represent legitimate therapeutic targets to ameliorate the cholinergic deficit. The two enzymes differ in location, substrate specificity and kinetics. Recent evidence suggests that BuChE may also have a role in the aetiology and progression of AD beyond regulation of synaptic ACh levels. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine, MF-8622) and ChE inhibitors such as rivastigmine, which have a dual inhibitory action on both AChE and BuChE, indicate potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. The development of specific BuChE inhibitors and the continued use of ChE inhibitors with the ability to inhibit BuChE in addition to AChE should lead to improved clinical outcomes.

Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some selected Nigerian medicinal plants

“…However, it has been speculated that this duality could lead to improved clinical outcomes, particularly in respect to the management of Alzheimer's disease (Greig et al, 2001). Thus the development of selective AChE inhibitors has been a primary challenge still confronting anticholinesterase pharmacology to date.…”

“…In this regard, BuChE could also scavenge anticholinesterase drugs, thereby elevating the dose necessary to achieve reasonable inhibitions at the target region of the brain for the effective therapeutic relief (Perry et al, 1996). While most researches have been geared towards identifying AChE selective inhibitors, recent results has suggest that inhibition of both AChE and BuChE should be one of the objectives in the treatment of cognitive dysfunctions associated with cases of AD (Greig et al, 2001). Several researches are now aimed at finding plants that inhibits both enzymes (Okello et al, 2004).…”

“…It has been suggested that inhibition of both enzymes may be important in the management of cognitive deficits associated with the AD (Greig et al, 2001, Ghayur et al, 2008) from our survey (unpublished work) some plants are used as memory enhansers and anti aging. Some of these plant are compiled and investigated for their AChE and BuChE inhibitory activities in order to ascertain their role in the traditional management of memory loss.…”

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

“…[17][18][19][20] It is suggested that BuChE is a key player in brain areas that influence the aggregation of neuritic Aβ plaques due to the correlation between BuChE polymorphisms and the progression of cognitive impairment in dementia with Lewy bodies (DLB) and AD. [21][22][23] It is also believed that BuChE is particularly important in individuals with more severe dementia, since its activity is increased with disease development. Therefore, compounds that can interact specifically with PAS or CAS residues are important in ChE inhibition and may help in prevention of Aβ aggregation facilitated by AChE.…”

In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes

“…Cholinesterase inhibitors increase both the level and duration of action of acetylcholine. In addition, it has been demonstrated that both acetylcholinesterase and butyrylcholinesterase (BChE) play an important role in Aβ-aggregation during plaque formation [3] . Many research papers published in the last decade have indicated that the structures of compounds that exhibit cholinesterase inhibitory activity are diverse [4,5] .…”