Human BuChE Research Articles

Anti-AChE and Anti-BuChE Screening of the Fermentation Broth Extracts from Twelve Aspergillus Isolates and GC-MS and Molecular Docking Studies of the Most Active Extracts.

Nowadays, the administration of cholinesterase enzyme (acetylcholinesterase: AChE and butyrylcholinesterase: BuChE) inhibitors is very common for the symptomatic treatment of Alzheimer's disease and the other forms of dementia and CNS disorders. In this paper, the anti-AChE and anti-BuChE activities of the fermentation broth ethyl acetate extracts from twelve Aspergillus isolates were evaluated by Ellman method. The results showed that A1 (Aspergillus flavus) and A5 (Aspergillus tubingensis, isolate 1) extracts with IC50 values of 46.77 μg/mL and 75.85 μg/mL possess the greatest ability to inhibit AChE and BuChE, respectively. GC-MS analysis of the extracts (A1 and A5) demonstrated that two alkaloids named 14-methyl-16-azabicyclo[10.3.1]hexadeca-1(15),12(16),13-triene (MAHT) and 6-chloro-2-methyl-7,8,9,10-tetrahydro-phenanthridine (CMTP) account for the highest percentage of A1 (26.95%) and A5 (25.5%) extracts, respectively. A 2-pyrazoline derivative, 5-hydroxy-3-(4-pyridinyl)-5-trifluoromethyl-1-(2,4,6-trimethylphenoxyacetyl)- (PHPTT), also constituted the high percentage (9.54%) of A5 extract. The anticholinesterase and neuroprotective effects of some 2-pyrazoline derivatives have been previously reported. The interaction study of MAHT with human AChE and CMTP and PHPTT with human BuChE using molecular docking indicated that these alkaloids bind to the active site gorge of the enzymes with high affinity. The best docking scores of MAHT, CMTP, and PHPTT were -7.1, -8.2, and -9.7 kcal/mol, respectively.

AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: Studies in cognitively poor middle-aged mice

The present work describes, for the first time, the in vivo effects of the multitarget compound AVCRI104P3, a new anticholinesterasic drug with potent inhibitory effects on human AChE, human BuChE and BACE-1 activities as well as on the AChE-induced and self-induced Aβ aggregation. We characterized the behavioral effects of chronic treatment with AVCRI104P3 (0.6μmolkg−1, i.p., 21 days) in a sample of middle aged (12-month-old) male 129/Sv×C57BL/6 mice with poor cognitive performance, as shown by the slow acquisition curves of saline-treated animals. Besides, a comparative assessment of cognitive and non-cognitive actions was done using its in vitro equipotent doses of huprine X (0.12μmolkg−1), a huperzine A-tacrine hybrid. The screening assessed locomotor activity, anxiety-like behaviors, cognitive function and side effects. The results on the ‘acquisition’ of spatial learning and memory show that AVCRI104P3 exerted pro-cognitive effects improving both short- and long-term processes, resulting in a fast and efficient acquisition of the place task in the Morris water maze. On the other hand, a removal test and a perceptual visual learning task indicated that both AChEIs improved short-term ‘memory’ as compared to saline treated mice. Both drugs elicited the same response in the corner test, but only AVCRI104P3 exhibited anxiolytic-like actions in the dark/light box test. These cognitive-enhancement and anxiolytic-like effects demostrated herein using a sample of middle-aged animals and the lack of adverse effects, strongly encourage further studies on AVCRI104P3 as a promising multitarget therapeutic agent for the treatment of cholinergic dysfunction underlying natural aging and/or dementias.

2-Arylbenzofuran-based molecules as multipotent Alzheimer's disease modifying agents

The complex etiology of Alzheimer's disease prompts scientists to develop multi-target strategies to combat causes and symptoms. In line with this modern paradigm and as a follow-up to our previous studies, we designed and synthesized a focused collection of new 2-arylbenzofurans and evaluated their biological properties towards specific targets involved in AD, namely human AChE and human BuChE, and Aβ fibril formation. Selected compounds were also tested for their ability to inhibit Aβ neurotoxicity in terms of neuronal viability loss, and to prevent Aβ peptide-binding to cell membrane and intracellular reactive oxygen species (ROS) formation. The different modifications introduced in the structure of our lead compound led to an increase in activity towards one or more of the selected targets: the anticholinesterase activity of some compounds was found to be significantly higher than previously obtained related molecules, and the compounds also proved to possess Aβ anti-aggregating properties and neuroprotective effects. The most interesting multi-target compounds were 18, and 1. Interestingly, 1 also showed good selectivity and moderate affinity for CB1 receptor, opening new perspectives in the field of research on AD, since cannabinoid ligands have been widely reported to have neuroprotective properties.

Studies of the amplification of carbaryl toxicity by various oximes

The administration of 2-pyridine aldoxime methyl chloride (2-PAM Cl) is a standard part of the regimen for treatment of human overexposure to many organophosphorus pesticides and nerve agents. However, some literature references indicate that poisoning by carbaryl (1-naphthyl N-methyl carbamate), an insecticide in everyday use, is aggravated by the administration of 2-PAM Cl. This effect has been reported in the mouse, rat, dog and man. We have found that the inhibition of both eel acetylcholinesterase (eel AChE, EC 3.1.1.7) and human serum cholinesterase (human BuChE, EC 3.1.1.8) by carbaryl was enhanced by several oximes. Based on 95% confidence limits the rank order of potentiation with eel AChE was TMB-4 = Toxogonin > HS-6 = HI-6 > 2-PAM Cl. By the same criterion, the rank order of potentiation with human BuChE was TMB-4 > Toxogonin > HS-6 = 2-PAM Cl. Carbaryl-challenged mice also reflected a potentiation since TMB-4 exacerbated the toxicity more than 2-PAM Cl. Our hypothesis is that certain oximes act as allosteric effectors of cholinesterases in carbaryl poisoning, resulting in enhanced inhibition rates and potentiation of carbaryl toxicity.