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      Combination Drug Therapy for the Management of Alzheimer’s Disease

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          Abstract

          Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meet clinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD.

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          Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

          Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.
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            Drug development in Alzheimer’s disease: the path to 2025

            The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.
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              Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options

              Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                05 May 2020
                May 2020
                : 21
                : 9
                : 3272
                Affiliations
                [1 ]Department of Pharmacy, BRAC University, Dhaka 1212, Bangladesh; tanvir_kbr@ 123456yahoo.com
                [2 ]Department of Pharmacy, Southeast University, Dhaka 1213, Bangladesh; aam.pharma@ 123456hotmail.com
                [3 ]Pharmakon Neuroscience Research Network, Dhaka 1207, Bangladesh
                [4 ]Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, P.O. Box 1039, 51687 Reims CEDEX 2, France; philippe.jeandet@ 123456univ-reims.fr
                [5 ]Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, F-25030 Besançon, France; lotfi.aleya@ 123456univ-fcomte.fr
                [6 ]Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; ramansouri@ 123456gmail.com
                [7 ]King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; ashraf.gm@ 123456gmail.com
                [8 ]Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
                [9 ]Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557, India; bijovilaventgu@ 123456gmail.com
                [10 ]Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11474, Saudi Arabia; may_binjumah@ 123456outlook.com
                [11 ]Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; abdeldaim.m@ 123456vet.suez.edu.eg
                [12 ]Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
                Author notes
                [* ]Correspondence: msu-neuropharma@ 123456hotmail.com ; Tel.: +880-171-022-0110
                Author information
                https://orcid.org/0000-0002-6078-8587
                https://orcid.org/0000-0002-0805-7840
                https://orcid.org/0000-0002-8774-5616
                https://orcid.org/0000-0003-3023-4871
                https://orcid.org/0000-0002-9820-2078
                https://orcid.org/0000-0002-3017-9924
                https://orcid.org/0000-0002-4341-2713
                Article
                ijms-21-03272
                10.3390/ijms21093272
                7246721
                32380758
                f59400cd-6ed2-406a-af66-ca1040c22155
                © 2020 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
                : 02 March 2020
                : 19 March 2020
                Categories
                Review

                Molecular biology
                combination therapy,dementia,alzheimer’s disease,multi-target-directed ligands

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