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Special Issue "Natural Products in Alzheimer’s Disease Drug Discovery"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editor

Special Issue Information

Dear Colleagues,

Despite over 50 years of intense drug discovery research on Alzheimer’s disease (AD), only four drugs of choices are currently available for its therapy: three acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine and galantamine) and one memantine which is the N-Methyl-D-aspartate (NMDA) antagonist. These drugs, developed over a decade ago, offer limited symptomatic relief while also causing numerous side effects. The frustration of drug discovery research for AD has further been evident in recent years from the high profile failure of late-stage clinical trials by big pharmaceutical companies for drug candidates that showed lots of promise in experimental models. In parallel with this tragedy, the economic and social costs of AD and dementia in general have only increased. In 2017, the estimated number of global dementia patients was 50 million people, while the projected estimate for 2030 and 2045 is around 82 million and 152 million, respectively. There is clearly a large faultline in the way we understand AD pathology and in the experimental models we employ to represent human pathology and our therapeutic approaches. It is against this background that this Special Issue was designed to underpin the pivotal role of natural products in drug discovery for human diseases. On this note, one of the existing anti-AD drugs, galantamine, was itself discovered from the common snowdrop plant, Galanthus nivalis. In many experimental models, the therpeutic potential of numerous natural products, both crude preparations and isolated compounds, have shown pharmacological efficacy not lower than the existing drugs. This include effects through unique biological targets (receptors, enzymes, ion chanelles, etc.) or multiple mechansims ranging from general antioxidants and antiinflammatory mechanisms, to neuroprotection and neuroregeneration processes. Insights into AD therapy using natural products in the form of original research articles or reviews in all areas of AD pathology, experimental designs and therapeutic approaches are welcome.

Prof. Solomon Habtemariam
Guest Editor

Manuscript Submission Information

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Keywords

  • Alzheimer’s disease
  • Dementia
  • Cholinergic hypothesis
  • Amyloid hypothesis
  • Natural products
  • Drug discovery
  • Monotherapy vs multitarget approach
  • Polytherapy vs single chemical entity
  • Experimental models of dementia
  • Novel bioassays for cognitive disorders

Published Papers (5 papers)

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Research

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Open AccessArticle
Synergistic Inhibition of Acetylcholinesterase by Alkaloids Derived from Stephaniae Tetrandrae Radix, Coptidis Rhizoma and Phellodendri Chinensis Cortex
Molecules 2019, 24(24), 4567; https://doi.org/10.3390/molecules24244567 - 13 Dec 2019
Abstract
Alkaloids having acetylcholinesterase (AChE) inhibitory activity are commonly found in traditional Chinese medicine (TCM); for example, berberine from Coptis chinensis, galantamine from Lycoris radiata, and huperzine A from Huperzia serrata. In practice of TCM, Stephaniae Tetrandrae Radix (STR) is often [...] Read more.
Alkaloids having acetylcholinesterase (AChE) inhibitory activity are commonly found in traditional Chinese medicine (TCM); for example, berberine from Coptis chinensis, galantamine from Lycoris radiata, and huperzine A from Huperzia serrata. In practice of TCM, Stephaniae Tetrandrae Radix (STR) is often combined with Coptidis Rhizoma (CR) or Phellodendri Chinensis Cortex (PCC) as paired herbs during clinical application. Fangchinoline from STR and coptisine and/or berberine from CR and/or PCC are active alkaloids in inhibiting AChE. The traditional usage of paired herbs suggests the synergistic effect of fangchinoline–coptisine or fangchinoline–berberine pairing in AChE inhibition. HPLC was applied to identify the main components in herbal extracts of STR, CR, and PCC, and the AChE inhibition of their main components was determined by Ellman assay. The synergism of herb combination and active component combination was calculated by median-effect principle. Molecular docking was applied to investigate the underlying binding mechanisms of the active components with the AChE protein. It was found that fangchinoline showed AChE inhibitory potency; furthermore, fangchinoline–coptisine/berberine pairs (at ratios of 1:5, 1:2, 1:1, and 2:1) synergistically inhibited AChE; the combination index (CI) at different ratios was less than one when Fa = 0.5, suggesting synergistic inhibition of AChE. Furthermore, the molecular docking simulation supported this enzymatic inhibition. Therefore, fangchinoline–coptisine/berberine pairs, or their parental herbal mixtures, may potentially be developed as a possible therapeutic strategy for Alzheimer’s patients. Full article
(This article belongs to the Special Issue Natural Products in Alzheimer’s Disease Drug Discovery)
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Open AccessArticle
Computational Study of Natural Compounds for the Clearance of Amyloid-Βeta: A Potential Therapeutic Management Strategy for Alzheimer’s Disease
Molecules 2019, 24(18), 3233; https://doi.org/10.3390/molecules24183233 - 05 Sep 2019
Cited by 2
Abstract
Alzheimer’s disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (Aβ) peptides in senile plaques. The interaction of Aβ and the receptor for advanced glycation end [...] Read more.
Alzheimer’s disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (Aβ) peptides in senile plaques. The interaction of Aβ and the receptor for advanced glycation end products at the blood-brain barrier is also observed in AD, which not only causes the neurovascular anxiety and articulation of proinflammatory cytokines, but also directs reduction of cerebral bloodstream by upgrading the emission of endothelin-1 to induce vasoconstriction. In this process, RAGE is deemed responsible for the influx of Aβ into the brain through BBB. In the current study, we predicted the interaction potential of the natural compounds vincamine, ajmalicine and emetine with the Aβ peptide concerned in the treatment of AD against the standard control, curcumin, to validate the Aβ peptide–compounds results. Protein-protein interaction studies have also been carried out to see their potential to inhibit the binding process of Aβ and RAGE. Moreover, the current study verifies that ligands are more capable inhibitors of a selected target compared to positive control with reference to ΔG values. The inhibition of Aβ and its interaction with RAGE may be valuable in proposing the next round of lead compounds for effective Alzheimer’s disease treatment. Full article
(This article belongs to the Special Issue Natural Products in Alzheimer’s Disease Drug Discovery)
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Open AccessArticle
Platycodigenin as Potential Drug Candidate for Alzheimer’s Disease via Modulating Microglial Polarization and Neurite Regeneration
Molecules 2019, 24(18), 3207; https://doi.org/10.3390/molecules24183207 - 04 Sep 2019
Abstract
Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer’s disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing [...] Read more.
Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer’s disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing brain microenvironment by small molecule-targeted microglia polarization and promoting neurite regeneration might be a potential therapeutic strategy for AD. In this study, we found platycodigenin, a naturally occurring triterpenoid, promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 and primary microglia. Platycodigenin downregulated pro-inflammatory molecules such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO), while upregulated anti-inflammatory cytokine IL-10. Further investigation confirmed that platycodigenin inhibited cyclooxygenase-2 (Cox2) positive M1 but increased Ym1/2 positive M2 microglial polarization in primary microglia. In addition, platycodigenin significantly decreased LPS-induced the hyperphosphorylation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 subunits. Furthermore, the inactivation of peroxisome proliferators-activated receptor γ (PPARγ) induced by LPS was completely ameliorated by platycodigenin. Platycodigenin also promoted neurite regeneration and neuronal survival after Aβ treatment in primary cortical neurons. Taken together, our study for the first time clarified that platycodigenin effectively ameliorated LPS-induced inflammation and Aβ-induced neurite atrophy and neuronal death. Full article
(This article belongs to the Special Issue Natural Products in Alzheimer’s Disease Drug Discovery)
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Open AccessArticle
Neuroprotective Effects of Red Ginseng Saponins in Scopolamine-Treated Rats and Activity Screening Based on Pharmacokinetics
Molecules 2019, 24(11), 2136; https://doi.org/10.3390/molecules24112136 - 06 Jun 2019
Abstract
Ginseng has been used to alleviate age-related dementia and memory deterioration for thousands of years. This study investigated the protective effect of red ginseng saponins against scopolamine-induced cerebral injury. Meanwhile, pharmacokinetics of ginsenosides in normal and scopolamine-treated rats were compared. After scopolamine injection, [...] Read more.
Ginseng has been used to alleviate age-related dementia and memory deterioration for thousands of years. This study investigated the protective effect of red ginseng saponins against scopolamine-induced cerebral injury. Meanwhile, pharmacokinetics of ginsenosides in normal and scopolamine-treated rats were compared. After scopolamine injection, glutathione, catalase and superoxide dismutase levels were significantly decreased when compared with control group. Compared with SA group, pretreatment of rats with red ginseng saponins could increase glutathione, catalase and superoxide dismutase level. Treatment with red ginseng saponins significantly decreased malondialdehyde level. In the pharmacokinetic analysis, a pattern recognition analysis method was used to investigate the pharmacokinetics of the absorbed compounds in blood. The pharmacokinetic parameters of Rg1, Rg2, Rh3, Rg5 and Rk1 in model group had higher area under the curve (AUC), mean residence time (MRT) and peak plasma concentration (Cmax) values; area under the curve (AUC) values and peak plasma concentration (Cmax) of model group was significantly different from that of normal group (p < 0.05). The Cmax value of Rk3, Rh1, Rh2 and Rh4 in model group was higher than normal group, but their AUC values were not significantly different. There was no significantly difference in time at Cmax (Tmax), AUC and Cmax values of Rb1, Rb2 Re, Rc, Rd and Rf between the model and normal group. 16 ginsenosides were grouped into three separate clusters according to principal component analysis (PCA) score plot based on pharmacokinetic data. The results suggested red ginseng saponins have significant protective effect against scopolamine-induced memory deficit and scopolamine-induced rats could lead to the changes of pharmacokinetic behaviors of ginsenosides. Full article
(This article belongs to the Special Issue Natural Products in Alzheimer’s Disease Drug Discovery)
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Review

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Open AccessFeature PaperReview
Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?
Molecules 2019, 24(8), 1519; https://doi.org/10.3390/molecules24081519 - 17 Apr 2019
Cited by 11
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Natural Products in Alzheimer’s Disease Drug Discovery)
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