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      Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

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          Abstract

          Alzheimer’s disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer’s disease drug to prevent, stop, or reverse its evolution is currently available. Current pharmacotherapy concentrated on drugs that aimed to improve the cerebral acetylcholine levels by facilitating cholinergic neurotransmission through inhibiting cholinesterase. These compounds, recognized as cholinesterase inhibitors, offer a viable target across key sign domains of Alzheimer’s disease, but have a modest influence on improving the progression of this condition. In this paper, we sought to highlight the current understanding of the cholinergic system involvement in Alzheimer’s disease progression in relation to the recent status of the available cholinesterase inhibitors as effective therapeutics.

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          Most cited references116

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          Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior.

          Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Update on Alzheimer's Disease Therapy and Prevention Strategies

            Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Aβ amyloid pathway and the tau pathway—leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD—continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy.
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              Cholinesterase inhibitors as Alzheimer's therapeutics

              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.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                26 December 2019
                January 2020
                : 10
                : 1
                : 40
                Affiliations
                [1 ]Grigore T. Popa” University of Medicine and Pharmacy, Center for Advanced Research and Development in Experimental Medicine (CEMEX), 16 Universitatii street, 700115 Iasi, Romania; gabriela-dumitrita.s@ 123456umfiasi.ro (G.D.S.); andrei.g.luca@ 123456umfiasi.ro (A.L.)
                [2 ]Grigore T. Popa” University of Medicine and Pharmacy, Pneumology Department, 16 Universitatii Street, 700115 Iasi, Romania
                [3 ]Grigore T. Popa” University of Medicine and Pharmacy, Pharmacodynamics and Clinical Pharmacy Department, 16 Universitatii street, 700115 Iasi, Romania; razvan.nicolae.rusu@ 123456gmail.com (R.N.R.); dana.ababei@ 123456gmail.com (D.C.A.)
                [4 ]University of Agricultural Sciences and Veterinary Medicine “Ion Ionescu de la Brad”, Faculty of Veterinary Medicine, 8 M. Sadoveanu Alley, 700489 Iasi, Romania; carmensolcan@ 123456yahoo.com
                [5 ]Grigore T. Popa” University of Medicine and Pharmacy, Department of Physiology, 16 Universitatii street, 700115 Iasi, Romania; waltherbild@ 123456gmail.com
                Author notes
                [* ]Correspondence: veronica.bild@ 123456gmail.com (V.B.); sbeschea@ 123456yahoo.com (S.I.B.C.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-4440-9628
                https://orcid.org/0000-0002-3628-4637
                Article
                biomolecules-10-00040
                10.3390/biom10010040
                7022522
                31888102
                012fe197-7054-449a-8001-075a29f00eb0
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 November 2019
                : 24 December 2019
                Categories
                Review

                alzheimer’s disease,cholinergic system,cholinesterase inhibitors,acetylcholinesterase,butyrylcholinesterase

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