Chapter 6 - Natural Compounds (Small Molecules) as Potential and Real Drugs of Alzheimer's Disease: A Critical Review

Abstract

In the introductory chapter, the critical review about the use of small molecules of natural origin deals with the consequences of pathophysiological processes of Alzheimer's disease (AD) as essential basis for rational intervention to moderation of this disease. Substantial attention is given to impact on β-amyloid (Aβ) production, undesirable destructive processes, which take place in central nervous system on the basis of Aβ activity, and possibilities of their affection (use of α-secretase elicitors, BACE1 inhibitors, antioxidants and scavengers, inhibitors of Aβ-induced neurotoxicity, and Aβ oligomer aggregation). Inhibitors of Aβ-induced inflammation of cells and agonists of PPARγ transcription factors also play significant role in this issue. During the AD progression, it is necessary to pay attention to τ-protein metabolism which is pathologically associated with tangles (glutaminyl cyclase inhibitors), and to interactions of Aβ with the receptors for final products of advanced glycation (inhibitors of RAGEs). Within the scope of cholinergic theory, the attention is paid on natural cognitive drugs (inhibitors of acetyl- and butyrylcholinesterase), substances improving brain metabolism (nootropics), and compounds affecting brain concentration of some neuromediators (inhibitors of prolyl endopeptidase). The antagonists of NMDA receptors and low molecular substances increasing metabolic turnover of NGF in brain tissue are very promising groups of substances which are still not frequently used in practice. Sensitive relationship between the effects of all three brain secretases, especially application of substances affecting γ-secretase, is frequently discussed. The inhibitors of GSK-3β are new group of compounds influencing metabolism of τ-protein and consecutive development of frontotemporal dementia. The substances which are perspective obviously (detailed results of preclinical trials are known, alternatively the substances which are in higher stages of clinical trials, and/or knowledge from their use is known) were chosen for this review. The practical possibilities of AD prevention with the use of natural substances, especially compounds with antioxidant activity, are discussed in this study. The effects which cannot be fulfilled are sometimes ascribed to these substances. The final part of the review includes prospects of research of small molecules of natural origin in twenty-first century according to the attention which is paid to them, that is, especially inhibitors of cholinesterases and nootropics, substances for inhibition of pathogenic fragments of Aβ formation, inhibition of aggregation and neuronal inflammation, inhibitors of secretases, and antagonists of NMDA receptors. The studies of moderation and/or prevention of ROS/Aβ recirculation cascade and progressive neurodegeneration, or more precisely the application of antioxidants, begin to play significant role too. The development of the study of GSK-3β inhibitors (an intense attention is paid on this glitazone receptor because of some controversial knowledge), agonists of PPARγ transcription factor, substances increasing synaptic transmission of acetylcholine, and inhibitors of prolyl endopetidase is promising.