Type Of Acetylcholinesterase Inhibitor Research Articles

Factors Affecting Rapid Cognitive Decline in Patients with Alzheimer's Disease: A Longitudinal Follow-Up Study.

We investigated the preventive and risk factors of rapid cognitive decline in patients with Alzheimer’s disease (AD). Using the Chang Gung Research Database (CGRD), we enrolled patients with AD aged over 65 years between 1 January 2001 and 30 May 2019, and followed up for at least two years. Rapid cognitive decline was defined by a Mini-Mental State Examination (MMSE) score decline of ≥4 in 2 years. A longer prescription of acetylcholinesterase inhibitors (AChEIs) was defined as 22 months based on the median treatment duration of the cohorts. The Cox proportional hazards regression model adjusted for age, sex, medication, and physical comorbidities was used to examine the candidate risk and protective factors. We analyzed data from 3846 patients with AD (1503 men, 2343 women) with a mean age and percentage of females of 77.8 ± 6.2 years and 60.9%, respectively. The mean duration of patients with AD receiving AChEIs was 658.7 ± 21.9 days. In general, 310 patients with AD showed a rapid cognitive decline, accounting for 8.1%. Treatment of a consecutive AChEI prescription for >22 months in patients with AD was a protective factor against rapid cognitive decline (adjusted hazard ratio (aHR) = 0.41, 95% confidence interval (CI) = 0.33–0.52, p < 0.001). Patients with AD aged >85 years (aHR = 0.53, 95% CI = 0.36–0.79, p < 0.01) and aged 75–85 years (aHR = 0.73, 95% CI = 0.57–0.93, p < 0.05) had a significantly lower risk of rapid cognitive decline than those aged 65–75 years. Additionally, patients with mild and moderate AD (clinical dementia rating (CDR = 1, aHR = 1.61, 95% CI = 1.26–2.07, p < 0.001; CDR = 2, aHR = 2.64, 95% CI = 1.90–3.65, p < 0.001) were more likely to have rapid cognitive decline than those with early AD (CDR = 0.5). Sex, medication with different types of AChEIs, and physical comorbidities were not associated with rapid cognitive decline. These findings indicate that it is important to maintain longer consecutive AChEI prescriptions in patients with AD to prevent cognitive decline.

Comparing Acetylcholinesterase and Butyrylcholinesterase Inhibition Effect of Total Extract and Fractions with Alcaloid-Rich Extract of Huperzia Serrata (Thunb.) Trevis.

Herbal extract, rich with natural compounds, has been used for medicinal purpose such as treating neurological disorders such as cognitive defection for a long period of time, often without significant adverse effects. We compared AChE and BuChE – inhibition effect of total extracts and fractions of Huperzia serrata (Thunb.) Trevis. with alcaloid-rich extract. Our samples were subjected under supersonic extraction with ethanol 50o as solvent and fractionally extracted with n-hexane, EtOAc and n-butanol, respectively; alcaloid-rich extract was collected simutaneously. Ellman’s method was used to assay AChE and BuChE inhibition activity. Results: Alcaloid-rich extraction proved to be the superior AChE inhibiting agent, its activity nearly 6 fold of the most active Huperzia serrata extraction with IC50 value of 7.93 (5.43-10.98) µg/ml. While the fractions as well as the total extract did not provide any BuChE inhibition activity, alcaloid-rich extract showed weak ability (IC50 at 76.67 (64.78 – 91.84) µg/ml). Overall, the superior enzyme inhibition effect of alcaloid-rich extract might open a new approach in preventing and treating neurological disorders such as alzheimer’s.&#x0D; Keywords&#x0D; Huperzia serrata (Thunb.) Trevis, alcaloid, Acetylcholinesrerase inhibitors (AChE); butyrylcholinesterase (BuChE), Alzheimer.&#x0D; References&#x0D; [1] Dos Santos Picanco, Leide C et al., Alzheimer's disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment, Current medicinal chemistry 25(26) (2018) 3141 - 3159. https://doi.org/10.2174/0929867323666161213101126.[2] B.M. McGleenon, K.B. Dynan, A.P. Passmore, Acetylcholinesterase inhibitors in Alzheimer's disease, British journal of clinical pharmacology 48(4) (1999) 471-480. https://10.1046/j.1365-2125.1999.00026.x.[3] Agneta Nordberg, Clive Ballard, Roger Bullock, Taher Darreh-Shori, Monique Somogyi, A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer’s disease, The primary care companion for CNS disorders 15(2) (2013). https://10.4088/PCC.12r01412.[4] N.M. Ha, V.V. Dung et al., Report on the review of Vietnam’s wildlife trade policy, 2007.[5] D.H. Bich, et al., Medicinal plants and medicinal animals in Viet Nam. Science and Technics Publishing House 1 (2011) 896-897 (in Vietnamese).[6] Jia-Sen Liu, Yuan-Long Zhu, Chao-Mei Yu, You-Zuo Zhou, Yan-Yi Han, Feng-Wu Wu, Bao-Feng Qi, The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity. Canadian Journal of Chemistry 64(4) (1986) 837-839. https://doi.org/10.1139/v86-137.[7] Takuya Ohba, Yuta Yoshino et al., Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice, Bioscience biotechnology and biochemistry 79(11) (2015) 1838-1844. https://doi.org/10.1080/09168451.2015.1052773.[8] Ju-Yeon Park, Hyuck Kim et al., Ethanol Extract of Lycopodium serratum Thunb. Attenuates Lipopolysaccharide-Induced C6 Glioma Cells Migration via Matrix Metalloproteinase-9 Expression, Chinese Journal of Integrative Medicine 24(11) (2018) 860-866. https://doi.org/10.1007/s11655-017-2923-9.[9] M. Maridass, G. Raju, Investigation of phytochemical and antimicrobial activity of Huperzia species, Pharmacologyonline 3 (2009) 688-692.[10] George.L.Ellman, K.Diane Courtney, et al., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochemical Pharmacology 7(2) (1961) 88-95. https://doi.org/10.1016/0006-2952(61)90145-9.[11] Paul T Francis, et al., The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery &amp; Psychiatry, 66(2) (1999) 137-147. http://dx.doi.org/10.1136/jnnp.66.2.137.[12] Prerna Upadhyaya, Vikas Seth, Mushtaq Ahmad, Therapy of Alzheimer’s disease: An update, African Journal of Pharmacy and Pharmacology 4(6) (2010) 408-421.[13] Hachiro Sugimoto, Hiroo Ogura, et al., Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor, The Japanese journal of pharmacology 89(1) (2002) 7-20.[14] N.T.K. Thu, et al., Acetylcholinesterase and butyrylcholinesterase inhibition effect of fractions extract of Huperzia serrata (Thunb.) Trevis. The journal of Pharmeceutical 56(11) 49-53 (in Vietnamese).[15] Xiaoqiang Ma, Changheng Tan, et al, Is there a better source of huperzine A than Huperzia serrata? Huperzine A content of Huperziaceae species in China. J Agric Food Chem, 53(5) (2005)1393-8. https://doi.org/10.1021/jf048193n.[16] Ya-Bing Yang, Xue-Qiong Yang, et al., A New Flavone Glycoside from Huperzia serrata. Chinese Journal of Natural Medicines 6(6) (2008) 408-410.[17] G.T. Ha, R.K. Wong, Y. Zhang, Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies, Chemistry &amp; biodiversity 8(7) (2011) 1189-1204. https://doi.org/10.1002/cbdv.201000269.[18] H.Y. Zhang, X.C. Tang, Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease, Trends in pharmacological sciences 27(12) (2006) 619-625. https://doi.org/10.1016/j.tips.2006.10.004.[19] Y. Wang, X.C. Tang, H.Y. Zhang, Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice, Journal of neuroscience research 90(2) (2012) 508-517. https://doi.org/10.1002/jnr.22775.[20] C.Y. Wang, et al., Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model, Neuropsychopharmacology 36(5) (2011) 1073-1089. https://doi.org/10.1038/npp.2010.245.[21] R.K. Gordon, et al., The NMDA receptor ion channel: a site for binding of Huperzine A, Journal of applied toxicology 21(S1) (2001) S47-S51. https://doi.org/10.1002/jat.805.[22] M. Rafii, et al., A phase II trial of huperzine A in mild to moderate Alzheimer disease, Neurology 76(16) (2011) 1389-1394. https://doi.org/10.1212/WNL.0b013e318216eb7b.[23] N.H. Greig, et al., A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase, Current medical research and opinion 17(3) (2001)1 59-165.[24] A. Ferreira, et al., Huperzine A from Huperzia serrata: a review of its sources, chemistry, pharmacology and toxicology, Phytochemistry reviews 15(1) (2016) 51-85. https://doi.org/10.1007/s11101-014-9384-y.

Differential Effects of Acetylcholinesterase Inhibitors on Clinical Responses and Cerebral Blood Flow Changes in Patients with Alzheimer's Disease: A 12-Month, Randomized, and Open-Label Trial

Background/Aims: The present study evaluated the differences in treatment outcomes and brain perfusion changes among 3 types of acetylcholinesterase inhibitors (AchEIs, i.e. donepezil, rivastigmine, and galantamine). Methods: This was a prospective, longitudinal, randomized, open-label, 3-arm (donepezil, rivastigmine, or galantamine), parallel-group, 12-month clinical trial carried out in 55 patients with AD. Results: At 6 months, the results of the Mini-Mental State Examination (MMSE) and the Trail Making Test (TMT)-Part A showed an improvement versus baseline in the donepezil treatment group. All groups showed a significant increase in regional cerebral blood flow (rCBF), mainly in the frontal lobe. Significant rCBF reduction was observed in the temporal lobe and cingulate gyrus in all 3 groups. Conclusion: AchEI treatment prevents the progression of cognitive impairment and increases the relative rCBF in the frontal lobe.

Effects of anticholinesterases on catalysis and induced conformational change of the peripheral anionic site of murine acetylcholinesterase

Conventional insecticides targeting acetylcholinesterase (AChE) typically show high mammalian toxicities and because there is resistance to these compounds in many insect species, alternatives to established AChE inhibitors used for pest control are needed. Here we used a fluorescence method to monitor interactions between various AChE inhibitors and the AChE peripheral anionic site, which is a novel target for new insecticides acting on this enzyme. The assay uses thioflavin-T as a probe, which binds to the peripheral anionic site of AChE and yields an increase in fluorescent signal. Three types of AChE inhibitors were studied: catalytic site inhibitors (carbamate insecticides, edrophonium, and benzylpiperidine), peripheral site inhibitors (tubocurarine, ethidium bromide, and propidium iodide), and bivalent inhibitors (donepezil, BW284C51, and a series of bis(n)-tacrines). All were screened on murine AChE to compare and contrast changes of peripheral site conformation in the TFT assay with catalytic inhibition. All the inhibitors reduced thioflavin-T fluorescence in a concentration-dependent manner with potencies (IC50) ranging from 8nM for bis(6)-tacrine to 159μM for benzylpiperidine. Potencies in the fluorescence assay were correlated well with their potencies for enzyme inhibition (R2=0.884). Efficacies for reducing thioflavin-T fluorescence ranged from 23–36% for catalytic site inhibitors and tubocurarine to near 100% for ethidium bromide and propidium iodide. Maximal efficacies could be reconciled with known mechanisms of interaction of the inhibitors with AChE. When extended to pest species, we anticipate these findings will assist in the discovery and development of novel, selective bivalent insecticides acting on AChE.

An electrochemical platform for acetylcholinesterase activity assay and inhibitors screening based on Michael addition reaction between thiocholine and catechol-terminated SAMs

An electrochemical platform for acetylcholinesterase (AChE) activity assay and its inhibitors screening is developed based on the Michael addition reaction of thiocholine, the hydrolysis product of acetylthiocholine (AsCh) in the presence of AChE, with the electrogenerated o-quinone of catechol-terminated SAMs on a gold electrode. For understanding and confirming the mechanism of the reaction, the electrochemical behaviors of Michael addition reaction of two model compounds, cysteine (CYS) and glutathione (GSH), towards the catechol-terminated SAMs have been studied. The enzyme kinetics and the inhibition effects of three types of AChE inhibitors, which are tacrine, carbofuran and parathion-methyl, have been investigated using an amperometric method. Among these three inhibitors, tacrine exhibits the strongest inhibiting effect, which is reinforced by the resulting data of kinetic studies on each inhibitor's influence upon the enzyme activity.

Study of PMS777, a new type of acetylcholinesterase inhibitor, in human HepG2 cells. Comparison with tacrine and galanthamine on oxidative stress and mitochondrial impairment

Acetylcholinesterase inhibitors are commonly used as cognitive enhancers for dementia in aged people. Among them, tacrine (THA) but not galanthamine, was shown to exhibit hepatotoxicity which reduces its clinical use. PMS777, both a PAF antagonist and a new potent acetylcholinesterase inhibitor was recently demonstrated to reverse scopolamine-induced amnesia in mice without toxicity. In the present study, the effects of THA, galanthamine and PMS777 were compared in HepG2 cells on the oxidative parameters involved in the reported hepatotoxicity of THA. THA (⩾10 μM) induced an oxidative stress as shown by elevated ROS and MDA production and by a decrease in GSH level. Moreover, mitochondrial membrane potential and redox status were decreased. At low concentrations (⩽10 μM), there was no significant disturbance. None of the oxidative stress markers was affected by PMS777 up to the maximum concentration tested and it is suggested that PMS777 is not cytotoxic for HepG2 cells. Galanthamine was also without cytotoxicity. Our results suggest that the toxic effect of THA above 10 μM may be caused by drug-induced mitochondrial energization impairment and destabilisation of membrane phospholipids associated with an oxidative stress. In contrast by preventing these dysfunctions, PMS777 could be safer than THA.

Differential effect of PMS777, a new type of acetylcholinesterase inhibitor, and galanthamine on oxidative injury induced in human neuroblastoma SK-N-SH cells

In the search for highly selective and potent cholinesterase inhibitors (AChEI) being able to improve oxidative injury, PMS777, a tetrahydrofuran derivative, was designed as a novel dual PAF and acetylcholinesterase inhibitor. The aim of this study was to investigate the modulatory effects of PMS777 and galanthamine, another AChEI, on the oxidative injury induced in neuronal cells. The SK-N-SH cells stimulated with LPS + IL- 1β were selected to investigate the direct inhibitory effect of PMS777 and galanthamine. LPS + IL- 1β induced oxidative injury as assessed by ROS production (29%), GSH depletion (11%) and loss of mitochondrial activity (22%). GSH depletion was never decreased by either drug. In contrast, ROS production and mitochondrial activity were totally prevented by addition of PMS777 but not galanthamine. PMS777 also inhibits butylcholinesterase and it shows selectivity for acetylcholinesterase. Thus, this PAF antagonist inaugurates a new type of AChEI, able to fight oxidative injury. Therefore, PMS777 could be of interest on patients with cognitive impairments and inflammatory damage, as in AD.

Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

A wide range of evidence shows that Cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer’s disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyryl-cholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.

Donepezil hydrochloride: a treatment drug for Alzheimer's disease.

The role of the cholinergic system with respect to cognitive deficits characteristic of Alzheimer's disease (AD) has led to a number of studies focusing on the development of acetylcholinesterase (AChE) inhibitors as a drug for treating this disease. The earliest known AChE inhibitors, namely, physostigmine and tacrine, performed poorly in clinical trials (e.g., poor oral activity, brain penetration, and hepatotoxic liability). Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action and with manageable adverse effects.

Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors.

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.

Structure-activity relationships of acetylcholinesterase inhibitors: Donepezil hydrochloride for the treatment of Alzheimer’s Disease

Abstract