The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a chronic disabling disease that affects the central nervous system. The main consequences of AD include the decline of cognitive functions and language disorders. One of the causes leading to AD is the decrease of neurotransmitter acetylcholine (ACh) levels in the brain, in part due to a higher activity of acetylcholinesterase (AChE), the enzyme responsible for its degradation. Many acetylcholinesterase inhibitors (AChEIs), both natural and synthetic, have been developed and used through the years to counteract the progression of the disease. The first of such drugs approved for a therapeutic use was tacrine, that binds through a reversible bond to the enzyme. However, tacrine has since been withdrawn because of its adverse effects. Currently, donepezil and galantamine are very promising AChEIs with clinical benefits. Moreover, rivastigmine is considered a pseudo-irreversible compound with anti-AChE action, providing similar effects at the clinical level. The purpose of this review is to provide an overview of what has been published over the last decade on the effectiveness of AChEIs in AD, analysing the most relevant issues under the clinical and methodological profiles and the consequent possible welfare effects for the whole world. Furthermore, novel drugs and possible therapeutic approaches are also discussed.

Therapeutic roles of plants for 15 hypothesised causal bases of Alzheimer’s disease

“…In the cholinergic hypothesis, memory dysfunction and the cause of AD are attributed to disruption of the cholinergic neurotransmitter system within the brain [ 266 – 268 ]. Cholinergic neurons produce the neurotransmitter acetylcholine (ACh), which mediates its action within the synapse and is then inactivated by the enzyme, acetylcholinesterase (AChE) [ 269 ].…”

“…AChEIs are also associated with lower risk of stroke and death [275,276]. A limitation is that AChEIs mediate adverse gastrointestinal symptoms at doses that are too low to be effective, and there are other adverse effects such as cardiac arrhythmia [268,277]. Hence there remains much room for improvement in this drug class [278], and a search for drugs with more CNS-selective AChE inhibition profiles [279] would be desirable.…”

Allicin, an Antioxidant and Neuroprotective Agent, Ameliorates Cognitive Impairment

“…Declined levels of neurotransmitter acetylcholine (Ach) by the action of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) also result in the onset of AD. The disease symptoms are mostly treated by the inhibition of these two enzymes [ 139 , 140 , 141 , 142 ]. Allicin has shown an inhibitory effect on the activity of AChE/BuChE enzymes.…”

Novel Neuroprotective Potential of Bunchosia armeniaca (Cav.) DC against Lipopolysaccharide Induced Alzheimer’s Disease in Mice

“…Additionally, the disorder causes significant memory loss as well as an inability to develop new memories, resulting in behavioral problems. AD is regarded as a multi-factorial disorder due to a combination of genetic and environmental variables [ 16 ]. There are seven opposing ideas linked to the start of AD: changes in the cholinergic system [ 17 , 18 ]; deposition of beta-amyloid aggregates caused by the incorrect breakdown of the precursor protein of amyloid (APP) [ 19 ]; hyperphosphorylation of tau proteins causing the formation of intracellular neurofibrillary tangles [ 20 ]; oxidative stress [ 21 , 22 ]; chronic peripheral [ 21 , 23 ] and neuro-inflammation [ 24 ] caused by microglial activation; high heavy metal concentrations [ 25 ], and metabolic disorders such as dysregulation of cholesterol homeostasis [ 26 ], type 2 diabetes, and obesity [ 27 ].…”