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      Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?

      review-article
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      Publication date (Electronic):
      Journal: Molecules
      Publisher: MDPI
      Keywords: Alzheimer’s disease, cholinergic, acetylcholinesterase, amyloid beta, anti-inflammatory, antioxidant, tau protein

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          Abstract

          Despite extensive progress in understanding the pathology of Alzheimer’s disease (AD) over the last 50 years, clinical trials based on the amyloid–beta (Aβ) hypothesis have kept failing in late stage human trials. As a result, just four old drugs of limited clinical outcomes and numerous side effects are currently used for AD therapy. This article assesses the common pharmacological targets and therapeutic principles for current and future drugs. It also underlines the merits of natural products acting through a polytherapeutic approach over a monotherapy option of AD therapy. Multi-targeting approaches through general antioxidant and anti-inflammatory mechanisms coupled with specific receptor and/or enzyme-mediated effects in neuroprotection, neuroregeneration, and other rational perspectives of novel drug discovery are emphasized.

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          Alzheimer's disease.

          Kaj Blennow, Mony J. de Leon, Henrik Zetterberg (2006)
          Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
          Article 0 comments Cited 872 times – based on 0 reviews     Review now
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            The cholinergic hypothesis of geriatric memory dysfunction.

            R T Bartus, R Dean, B Beer … (1982)
            Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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              Memantine in moderate-to-severe Alzheimer's disease.

              Barry Reisberg, Rachelle Smith Doody, Albrecht Stöffler … (2003)
              Overstimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate is implicated in neurodegenerative disorders. Accordingly, we investigated memantine, an NMDA antagonist, for the treatment of Alzheimer's disease. Patients with moderate-to-severe Alzheimer's disease were randomly assigned to receive placebo or 20 mg of memantine daily for 28 weeks. The primary efficacy variables were the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev). The secondary efficacy end points included the Severe Impairment Battery and other measures of cognition, function, and behavior. Treatment differences between base line and the end point were assessed. Missing observations were imputed by using the most recent previous observation (the last observation carried forward). The results were also analyzed with only the observed values included, without replacing the missing values (observed-cases analysis). Two hundred fifty-two patients (67 percent women; mean age, 76 years) from 32 U.S. centers were enrolled. Of these, 181 (72 percent) completed the study and were evaluated at week 28. Seventy-one patients discontinued treatment prematurely (42 taking placebo and 29 taking memantine). Patients receiving memantine had a better outcome than those receiving placebo, according to the results of the CIBIC-Plus (P=0.06 with the last observation carried forward, P=0.03 for observed cases), the ADCS-ADLsev (P=0.02 with the last observation carried forward, P=0.003 for observed cases), and the Severe Impairment Battery (P<0.001 with the last observation carried forward, P=0.002 for observed cases). Memantine was not associated with a significant frequency of adverse events. Antiglutamatergic treatment reduced clinical deterioration in moderate-to-severe Alzheimer's disease, a phase associated with distress for patients and burden on caregivers, for which other treatments are not available. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 17 April 2019
                Publication date Collection: April 2019
                Volume: 24
                Issue: 8
                Electronic Location Identifier: 1519
                Affiliations
                Pharmacognosy Research Laboratories & Herbal Analysis Services UK, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK; s.habtemariam@ 123456herbalanalysis.co.uk ; Tel.: +44-208-331-8302/8424
                Article
                Publisher ID: molecules-24-01519
                DOI: 10.3390/molecules24081519
                PMC ID: 6514598
                PubMed ID: 30999702
                SO-VID: c6ff4ab0-3a72-446c-a4ce-7f34cfbbb98f
                Copyright © © 2019 by the author.
                License:

                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
                Date received : 02 April 2019
                Date accepted : 16 April 2019
                Categories
                Subject: Review

                Keywords: alzheimer’s disease,cholinergic,acetylcholinesterase,amyloid beta,anti-inflammatory,antioxidant,tau protein
                Data availability:
                Keywords: alzheimer’s disease, cholinergic, acetylcholinesterase, amyloid beta, anti-inflammatory, antioxidant, tau protein

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