Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 5

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2017
• Print ISBN:
  9781681085869
• eBook ISBN:
  9781681085852
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the eBook series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology. The fifth volume of this series features reviews that cover the following topics:
-drug treatment for spinal cord injury
-action tremors
-natural products for Alzheimer's disease treatment
-non pharmacological approaches towards pain management
-biosensors for detecting neurodegenerative diseases
-NMDA receptor targeting
-alkaloid antidepressants

Natural Products for the Treatment of Alzheimer’s Disease: Present and Future Expectations

Fernanda Rodríguez-Enríquez, Iria Torres, Dolores Viña^*

Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain

Abstract

Improving living conditions and health care in developed countries has significantly increased life expectancy, which has led to an increase in age related disorders. In the population older than 60 years old the majority of cases of dementia are Alzheimer disease (AD). Progressive neurodegeneration in AD induces cognitive deterioration and constitutes a serious social problem. Currently, the drugs approved for the treatment of AD just slow down the progression of the disease or have a symptomatic effect. They are mainly acetylcholinesterase inhibitors (AChEIs) as donepezil, rivastigmine and galantamine or NMDA-receptor antagonist such as memantine. These drugs modestly improvement cognition, daily life activities and behavior in patients ranging from mild to severe stages of the disease. However, none of these agents has proven to be able to stop or reverse the underlying neurodegenerative process. Different studies point out that environmental factors and life style, such as diet and exercise have an important role in the biological mechanisms of the pathophysiology, considering them mutable. Actually, dietary compounds have been studied as therapeutics for neurodegenerative diseases and numerous studies have been focused on different nutritional approaches to benefit AD patients. On the other hand, during decades, medicinal plants have been studied as a potential treatment for dementia. This chapter includes a review of different natural products such as fatty acids, vitamins, alkaloids, amino acids, hormones and diverse groups of polyphenolic plant secondary metabolites, among others, which have a potential role in the prevention or treatment of AD.

Keywords: Alzheimer’s disease, Dementia, Natural products, Neuroprotection, Pharmacological activity.

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^* Corresponding author Dolores Viña: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain; Tel/Fax: [phone]; Email: [email protected]

Introduction

Improving living conditions and health care in developed countries has significantly increased life expectancy, which has led to an increase in age related

disorders. In the population older than 60 years dementia is mainly attributable to Alzheimer’s disease (AD). Currently 35 million people has AD and by 2050 is estimated that this value will be, at least, triplicated [1, 2]. This disease is accompanied by a progressive neuropsychiatric disorder, which implies gradual cognitive decline and a decrease in the ability to accomplish normal daily living activities as well as progressive behavioral disturbances [3].

Although mild cognitive impairment (MCI) is considered a common stage both in aging and dementia, it is a risk state that does not necessarily lead to AD. Some symptoms such as depressive state and anxiety in patients with MCI have been linked with a major probability to progress from MCI to AD [4, 5]. Requirements suggested to introduce MCI drugs in the market by the European Medicines Agency as well as US Food and Drug Administration (FDA), include how to diagnose it with precise parameters and how to discriminate and recognize signs of future AD outbreak [6, 7]. Nowadays, the trials that have been carried out did not show any remarkable amelioration on AD dementia onset and evolution [8]. Thus, MCI lacks interest as a clinical target.

Currently approved treatments by FDA, includes five drugs for the cognitive manifestations of AD. Four of them are the AChEI such as rivastigmine (Exelon^TM), galantamine (Razadyne^TM, Reminyl^TM), tacrine (Cognex^TM) and donepezil (Aricept^TM) since in the course of AD there is a substantial loss in cholinergic neurons. Tacrine (Cognex^TM) is rarely prescribed because of its serious side effects related to liver damage. The fifth one is memantine (Namenda^TM), which acts as antagonist of N-methyl-D-aspartate (NMDA) receptor and it is the only drug authorized for more advances stages of the diseases that shows effectiveness [9]. All these market drugs slow down modestly the advance of cognitive symptoms, however they produce diverse side effects and do not stop the death of brain cells [10].

Therapeutic strategies for AD relying on one specific mechanism have not resulted to date due to the complexity of the pathophysiological mechanisms involved in this disease. Therefore, the research of new drugs which act in multiple pathomechanisms of AD is needed.

Diet is a relevant factor in maintaining the mental capacities during the aging process. Thus, malnutrition increases the risk of developing MCI and AD. Some epidemiological studies related to neurodegenerative disease factors highlight the influence of nutritional deficiencies on the risk of suffering these diseases [11]. Accordingly, a nutrition based on vegetables, antioxidants and polyunsaturated fats, such as the Mediterranean one, has been seen as an element which could decrease the risk of MCI and AD [12]. Through this chapter, we will describe some natural compounds whose therapeutic administration could possibly inhibit and prevent the AD outbreak or at least reduce the speed of its development. However, further research on the potential of these and other natural substances is needed to establish whether they actually constitute a remedy for AD and other neurodegenerative disorders.

Pathophysiology of AD

Structural modifications especially in cortex, basal forebrain nuclei and hippocampus have been identified as pathological hallmarks of AD [13]. These modifications which are mainly characterized by intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated Tau proteins and extracellular senile plaques that are formed by aggregated β-amyloid peptide (Aβ), cause the loss of cholinergic synapses resulting in a harsh decrease of cholinergic tone [14].

In fact, Aβ deposits have been postulated as the elementary cause of AD and it has been experimentally demonstrated that neurophysiological modifications that are thought to be associated with AD’s synaptic dysfunction can be initiated by neuronal exposure to very small concentrations of Aβ oligomers [15]. Therefore, the harmful effects on synapses and mitochondria are caused by the oxidative stress induced by Aβ₄₂ oligomers and Tau hyperphosphorylation [16, 17]. Aβ levels in the brain are regulated by several mechanisms: phagocytic clearance by microglia [18] and astrocytes [19], transport through the blood-brain-barrier (BBB) by various cell surface receptors, including the scavenger receptor RAGE (receptor for advanced glycation end-products) expressed on brain endothelium [20] and production or degradation by enzymes [21]. When β- and γ-secretases process the amyloid precursor protein (APP) cause an exaggerated storing of Aβ in the cortex and hippocampus in AD brain. However, APP can be alternatively cleaved by α-secretase pathway originating the soluble amyloid precursor α (sAPPα), which has some neuroprotective activities given that it facilitates axon growth ...

Table of contents

• Welcome
• Table Of Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• PREFACE
• List of Contributors
• Drug Treatment for Spinal Cord Injury
• Essential Tremor: The Current State and Challenges
• Natural Products for the Treatment of Alzheimer’s Disease: Present and Future Expectations
• Pain Management Strategies: Some Uses of Antidepressant Medications and Non-Pharmacological Approaches
• Biosensors for Detection of Neurotransmitters and Neurodegenerative Related Diseases
• NMDA Receptor as a Molecular Target for Central Nervous System Disorders: The Advances and Contributions of Molecular Modeling
• Therapeutic Potential of Plant Alkaloids as Antidepressant