6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer’s disease

Abstract

BACKGROUND:Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aβ production and clearance, resulting in increased amount of Aβ in various forms [2]. Reduction of Aβ production and increasing clearance of Aβ pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Aβ fi brils in vitro and Aβ plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Aβ and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Aβ-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. OBJECTIVE:To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease. METHODS:In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Aβ1−40 aggregation was studied using a thiofl avin T (ThT) fl uorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.

Inhibition of tissue transglutaminase promotes Aβ-induced apoptosis in SH-SY5Y cells

“…Moreover, Aβ was added to mimic an AD pathological condition because it is involved in protein aggregation and neural toxicity in AD pathogenesis [37][38][39] . tTG and its product isopeptide were detected by Western blot analysis at different molecular weights or by in-cell Western assays.…”

Recent Advances in the Quest for Treatment and Management of Alzheimer and Other Dementia

“…Their experiments revealed that nasal administration of Memogain efficiently transported the drug to the brain with the possibility to inhibit deposition of plaque and enhance behavioral symptoms in AD. Another novel sequence of flavonoid based compound was designed and produced which showed AChEI activity along with advanced glycation end products (AGEs) inhibitory properties and antioxidant potential as well[95].One compound 6-methyluracil derivative was found capable of passing through the blood-brain barrier, enhanced working memory in transgenic mice with amyloid precursor protein/PS1 and considerably decreased the Aβ plaques number and area in the brain[96]. Another compound, β-asarone notably enhanced the learning and memory of APP/PS1 transgenic mice by suppressing Beclin-1-dependent autophagy via the PI3K/Akt/mTOR pathway[97].…”