Frontiers in Clinical Drug Research - Alzheimer Disorders: Volume 5

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2016
• ISBN:
  9781681082318
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research - Alzheimer Disorders is an e-Book series concerned with Alzheimer's disease (AD) that causes dementia, or loss of brain function. The disease affects the parts of the brain that deal with memory, thought, and language. Chapters in each volume focus on (Alzheimer Disorders) drug research with special emphasis on clinical trials, research on drugs in advanced stages of development and cure for Alzheimer's disease and related disorders. Frontiers in Clinical Drug Research - Alzheimer Disorders will be of particular interest to readers interested in drug therapy of this specific neurodegenerative condition and related brain disorders as the series provides relevant reviews written by experts in field of Alzheimer's Disease research. The fifth volume of this series features chapters covering critical discussions on AD management and new therapies. The topics reviewed in this volume include:
- Current concepts in management of AD
- The amyloid cascade hypothesis and stem cell-based AD therapy
- Phytochemicals targeting AD
- Dementia screening in primary clinical care settings
- Updates in dementia / AD clinical research and drug development

Natural Compounds from Plants Targeting Alzheimer’s Disease

Andreia Corciova¹, Daniela Matei^{2, *}, Calin Corciova², Bianca Ivănescu³

¹ Department of Drugs Analysis, Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania

² Department of Biomedical Sciences, Faculty of Biomedical Engineering, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania

³ Department of Pharmaceutical Botany, Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania

Abstract

Alzheimer’s disease is a common form of dementia. Drugs currently available for treatment of Alzheimer’s disease are only symptomatic and act by augmenting the level of acetylcholine. These drugs do not stop or delay the evolution of disease and manifest specific adverse effects that limit their use. In this context, it is crucial the development of new drugs that will target the causal agent of disease. Such compounds that intervene at different levels in the pathogenesis of Alzheimer’s disease were identified in plant extracts.

In this chapter, we propose an overview of some compounds that have anti-amyloidogenic activity of which the most important are: curcuminoids, ellagic acid, gallic acid, salvianolic acid B, resveratrol and epicagallocatechin-3-gallate. Besides the mechanism and biological actions, this chapter will present the vegetal products from which the active compounds are extracted, methods of extraction, identification and quantification. Selected techniques will be compared in terms of optimal conditions for extraction. Moreover, methods for identification and quantification will be described in terms of analytical conditions. Nature remains an important resource of active molecules and a hope in treating Alzheimer’s disease.

Keywords: Alzheimer’s disease, Methods of extraction, Oxidative stress, Solvents, Vegetal products.

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^* Corresponding author Daniela Matei: Department of Biomedical Sciences, Faculty of Medical Bioengineering, “Grigore.T.Popa” University of Medicine and Pharmacy. 9-13 Kogalniceanu Street, 700454, Iasi, Romania; Tel/Fax: [phone]; Cell: [phone]; E-mails: [email protected], [email protected].

INTRODUCTION

Alzheimer’s disease, named after the neurologist Alois Alzheimer (1864-1915) is a type of dementia characterized by a deterioration of mental capacity, which installs with age. Increasing life expectancy increases the risk of this disease.

Worldwide there are currently 24.3 million people with dementia and 4.6 million new cases are diagnosed annually. It is estimated that the number of people with dementia doubles every 20 years and for 2050 it is forecast to be 115 million people suffering from AD [1].

Hallmark brain abnormalities in AD are the formation of the senile plaques and neurofibrillary degeneration, processes that gradually causes the death of neurons, especially in the brain structures involved in cognitive processes such as frontal cortex, hippocampus, basal nucleus of Meynert [2].

Drugs currently available for treatment of Alzheimer’s disease are only symptomatic and act by augmenting the level of acetylcholine, compensating for loss of cholinergic function: acetylcholine precursors, muscarinic agonist, nicotinic agonists and choline esterase inhibitors [2].

These drugs do not stop or delay the evolution of disease and manifest specific adverse effects that limit their use. In this context, the development of new drugs that will target the causal agent of disease is crucial.

Such compounds that intervene at different levels in the pathogenesis of Alzheimer’s disease were identified in plant extracts.

In this chapter we propose an overview of the curcuminoids, ellagic acid, gallic acid, galagic acid salvianolic acid B, rosmarinic acid, punicallagin, resveratrol, epicagallocatechin-3-gallate, oleanolic acid, oleuropein, ginkgolide and biblobalide. These compounds act through diverse mechanisms in blocking the amyloid cascade: by stopping the aggregation of amyloid beta peptide and fibril formation, promoting the disaggregation of formed fibrils, inhibiting beta-secretase and gamma-secretase or increasing alpha-secretase activity, thus increasing the production of non-amyloidogenic peptide.

Knowing that beta-amyloid peptide damages neurons by generating reactive oxygen species in the process of self-aggregation, the antioxidant activity of plant compounds must be taken into account as well. The majority of tests highlighting anti-amyloidogenic activities of natural compounds were performed in vitro, so further research is needed for confirmation of these activities in vivo and clinical trials for introduction of new drugs in therapy.

Besides the mechanism and biological actions, this chapter will present the vegetal products from which the active compounds are extracted, methods of extraction, identification and quantification. Selected techniques will be compared in terms of optimal conditions for extraction, such as solvents, modifiers used to improve the extraction, temperature, pressure and extraction time. Moreover, methods for identification and quantification will be described in terms of analytical conditions: derivatization of compounds, stationary and mobile phase, temperature, detector type, analysis time, limit of detection, limit of quantitation, correlation between the method/extraction solvent and the recovered concentration.

Knowing the different types of analysis methods that can be used for the extraction, separation, identification and quantification of proposed compounds is of great importance, the analysts can choose the most suitable and effective technical conditions, taking into account the available equipment.

Considering the fact that natural compounds have fewer side effects, are well tolerated and can be further used as models for the synthesis of novel drugs, nature remains an important resource of active molecules and a hope in treating Alzheimer’s disease.

PATHOPHYSIOLOGICAL MECHANISMS

Beta-Amyloid and Tau Proteins

The best known pathophysiological mechanisms involved in AD are increased concentration of aggregated proteins, reduced synthesis of neurotransmitters, mitochondria dysfunction, oxidative stress, inflammation, alteration in the metabolism of iron, endothelial and insulin dysfunction.

The beta-amyloid (Aβ) protein is obtained during the cleavage of the amyloid precursor protein (APP) by alpha (α), gamma (γ), and beta (β) secretases. The cleavage of APP by β and γ–secretases creates Aβ42 peptide, which is considered neurotoxic, and the cleavage by α-secretase produce Aβ40 [3]. The Aβ peptide forms oligomers and then aggregate as amyloid plaques.

Tau protein serves to stabilize microtubules through phosphorylation and also provides axonal transport [4]. Tau protein becomes hyperphosphorylate in AD, which contributes to the destruction of microtubules, aggregates to form neurofibrillary tangles (NTFs), impairs axonal transport and neuronal cell apoptosis [5].

Neurotransmitters

The oldest hypothesis underlying pathophysiological mechanisms of AD is the “cholinergic hypothesis” suggesting that AD begins as a deficiency in the production of acetylcholine [6]. Acetylcholine has been shown to regulate diverse processes in the brain, ...