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      The Potential Use of Plant Natural Products and Plant Extracts with Antioxidant Properties for the Prevention/Treatment of Neurodegenerative Diseases: In Vitro, In Vivo and Clinical Trials

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          Abstract

          Neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, present a major health issue and financial burden for health care systems around the world. The impact of these diseases will further increase over the next decades due to increasing life expectancies. No cure is currently available for the treatment of these conditions; only drugs, which merely alleviate the symptoms. Oxidative stress has long been associated with neurodegeneration, whether as a cause or as part of the downstream results caused by other factors. Thus, the use of antioxidants to counter cellular oxidative stress within the nervous system has been suggested as a potential treatment option for neurological disorders. Over the last decade, significant research has focused on the potential use of natural antioxidants to target oxidative stress. However, clinical trial results have lacked success for the treatment of patients with neurological disorders. The knowledge that natural extracts show other positive molecular activities in addition to antioxidant activity, however, has led to further research of natural extracts for their potential use as prevention or treatment/management of neurodegenerative diseases. This review will cover several in vitro and in vivo research studies, as well as clinical trials, and highlight the potential of natural antioxidants.

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          Antioxidant and prooxidant properties of flavonoids.

          The interest in possible health benefits of flavonoids has increased owing to their potent antioxidant and free radical scavenging activities observed in vitro. Nevertheless, the antioxidant efficacy of flavonoids in vivo is less documented and their prooxidant properties have been actually described in vivo. Due to their prooxidant properties, they are able to cause oxidative damage by reacting with various biomolecules, such as lipids, proteins and DNA. Hence, the aim of this review is to discuss both the antioxidant and prooxidant effects of flavonoids. Copyright © 2011 Elsevier B.V. All rights reserved.
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            A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease.

            Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.
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              Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier.

              Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O(2), scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                11 December 2018
                December 2018
                : 23
                : 12
                : 3283
                Affiliations
                School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen AB10 7GJ, UK; f.pohl@ 123456rgu.ac.uk
                Author notes
                [* ]Correspondence: p.v.s.kong-thoo-lin@ 123456rgu.ac.uk ; Tel.: +44-122-426-2818
                Article
                molecules-23-03283
                10.3390/molecules23123283
                6321248
                30544977
                2290cb6e-d42a-41cd-a6d7-c4841461e997
                © 2018 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
                : 08 November 2018
                : 30 November 2018
                Categories
                Review

                antioxidants,natural products,in vitro,in vivo,clinical trials,plant extracts,phytochemicals,phenolics,ginkgo biloba,secondary metabolites

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