Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Abstract

Alzheimer's disease (AD) is one of the most common forms of dementia. AD is a chronic syndrome of the central nervous system that causes a decline in cognitive function and language ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed for the treatment of AD, including naturally-derived inhibitors, synthetic analogues and hybrids. Currently, the available drugs for AD are predominantly cholinesterase inhibitors. However, the efficacy of these drugs is limited as they may cause adverse side effects and are not able to completely arrest the progression of the disease. Since AD is multifactorial disease, dual and multi-target inhibitors have been developed. The clinical applications and the limitations of the inhibitors used to treat AD are discussed in the present review. Additionally, this review presents the current status and future directions for the development of novel drugs with reduced toxicity and preserved pharmacological activity.

Chemical Profiling and Biological Properties of Extracts from Different Parts of Colchicum Szovitsii Subsp. Szovitsii

“…Cholinesterase inhibitors are known to enhance cognitive function by inhibiting the enzymes that degrade acetylcholine in the brain and this approach is known as cholinergic hypothesis. Cholinesterase inhibitors have always been a significant therapeutic target for the treatment of Alzheimer's disease [33]. As shown in Table 3, the methanolic extracts obtained using maceration and Soxhlet of the C. szovitsii subsp.…”

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

“…At the cellular level, the neuronal choline deficiency initially suggested by Wurtman [24] and attested by some facts that a 40%-50% decrease in cerebral acetylcholine level, a decrease in choline-dependent membrane constituents, and increase in its metabolites, is considered a pathogenic element for dementia and AD. It has been hypothesized that, under conditions of choline deficiency, for the recovery of the necessary choline, a true "auto-cannibalism" of the membranous choline, which favors cell membrane to break with the release of enzymes that cause an abnormal proteolysis of the β-amyloid precursor protein and the formation of amyloid protein β-A4, a highly harmful complex by the effect of neuronal degeneration, that this amyloid has on a primary culture of neurons [14,22,24,25]. The pathogenic hypothesis regarding choline deficiency has at least two corollaries: One diagnostic, by the possibility of determining the concentration of choline derivatives in cerebrospinal fluid (CSF), and the other therapeutic by using potassium channel inhibitors in order to enhance the synthesis of choline and increase acetylcholine uptake.…”

“…AchE has been shown to be the most important therapeutic target for the symptomatic improvement of AD, since its inhibition was considered to be achievable as a therapeutic target. There are two types of cholinesterase, acetylcholinesterase (mainly present in blood and neuronal synapses) and butyrylcholinesterase (mainly in the liver) and the difference between the two is represented by substrates [19,25]. Acetylcholinesterase exists in two general classes of molecular forms: Simple homomeric oligomers of catalytic subunits (monomers, dimers, and tetramers) and heteromeric associations of catalytic subunits with structural subunits.…”

“…Acetyl CoA is highly labile to hydrolysis after which acetate and the active enzyme are formed. AchE is one of the most efficient enzymes known: One molecule of AchE can hydrolyze 6x105 molecules of acetylcholine/minute; thus, the recovery time of the enzyme is 100 microseconds [25,29].…”

“…The acetylcholine receptors (cholinergic receptors) have been designated according to the selective pharmacological ligands (muscarinic and nicotine), in muscarinic and nicotinic. The cellular effectors of these receptors are sodium ion channels and membrane proteins modulated by G proteins [14,19,25].…”