Topic Editors

Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
Prof. Dr. Wei-Jan Huang
Graduate institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

Bioactive Natural Products and Synthetic Small Molecules as Potential Investigational Treatments for Neurodegenerative Diseases

Abstract submission deadline
closed (31 October 2022)
Manuscript submission deadline
closed (31 December 2022)
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Topic Information

Dear Colleagues,

The prevalence of Alzheimer’s disease (AD) is continuously growing worldwide, which leads to great social–economic burdens. Despite the great therapeutic improvement researchers have achieved in the past few decades, novel treatments targeting Alzheimer’s disease remain an urgent need. AD is a progressive neurodegenerative disorder, and patients are characterized by dysfunctions of behaviors, memories, and spatial awareness and, in the late stage, loss of ability to participate in general activities. The neuropathology may involve protein abnormalities of neurofibrillary tangles of tau proteins and senile amyloid plaques of amyloid b peptides (Ab), and neuronal and synaptic losses and accompanying lower levels of acetylcholine, inflammations, and oxidative damages. The “amyloid hypothesis” is the main AD etiology for the imbalance of production and clearance of Ab, which aggregates and then accumulates to initiate AD progress. Reactive oxygen species (ROS) and free radicals are associated with aging based on the “free radical theory of aging”. Although researchers have devoted themselves to developing small molecules and monoclonal antibodies as AD treatments in recent decades, none so far have been clinically successful in cognition improvement. The poor outcome is due to the multifactorial pathogenetic mechanism of AD, and to date, the only approved therapeutic drugs for clinical AD treatments are acetylcholinesterase (AChE) inhibitors, which are developed based on the “cholinergic hypothesis”, and one N-methyl-D-aspartate (NMDA) receptor antagonist. While these drugs have shown short-term benefits in improving symptoms, however, they have not been found to be able to reverse or delay AD progression. This clearly indicates that an unmet medical need exists in AD. The scope of this Research Topic is to investigate the potential efficacy, pharmacokinetics, and underlying mechanisms of natural products or synthetic compounds against Alzheimer’s disease using modern tools on the following subtopics but not limited to: Subtopics: Small molecular drugs and medicinal plants potentially against Alzheimer’s disease, and the in vivo pharmacokinetic properties; AChE inhibitory assay and molecular docking with AChE; Ab aggregation, tau protein hyperphosphorylation and neurofibrillary tangles, reactive oxygen species, neuron or microglia inflammation and their roles in neurodegeneration in cell or animal models; In vitro and/or in vivo models studying natural products, synthetic compounds, or derivatives.

Prof. Dr. Wen-Chi Hou
Prof. Dr. Wei-Jan Huang
Dr. Rita P.-Y. Chen
Topic Editors

Keywords

  • Alzheimer’s disease
  • amyloid beta
  • antioxidant
  • reactive oxygen species
  • tau protein
  • cell line experiment
  • animal models
  • bioactive natural products
  • synthetic compounds or derivatives
  • medicinal chemistry
  • computational chemistry

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
BioMed
biomed
- - 2021 20.3 Days CHF 1000
Biomedicines
biomedicines
3.9 5.2 2013 15.3 Days CHF 2600
Current Issues in Molecular Biology
cimb
2.8 2.9 1999 16.8 Days CHF 2200
Neurology International
neurolint
3.2 3.7 2009 22.1 Days CHF 1600
Methods and Protocols
mps
2.3 3.6 2018 24.9 Days CHF 1800

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Published Papers (10 papers)

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14 pages, 3504 KiB  
Article
Nitro Capsaicin Suppressed Microglial Activation and TNF-α-Induced Brain Microvascular Endothelial Cell Damage
by Sopana Jamornwan, Tanida Chokpanuwat, Kwanchanok Uppakara, Thanet Laorob, Uthai Wichai, Pimonrat Ketsawatsomkron and Witchuda Saengsawang
Biomedicines 2022, 10(11), 2680; https://doi.org/10.3390/biomedicines10112680 - 23 Oct 2022
Cited by 2 | Viewed by 1976
Abstract
Chronically activated microglia and brain vascular damage are major causes of neuroinflammation. The aim of this study was to determine the anti-inflammatory effects of nitro capsaicin, a newly modified capsaicin with less irritating characteristics, against microglial activation and brain microvascular endothelial cell damage. [...] Read more.
Chronically activated microglia and brain vascular damage are major causes of neuroinflammation. The aim of this study was to determine the anti-inflammatory effects of nitro capsaicin, a newly modified capsaicin with less irritating characteristics, against microglial activation and brain microvascular endothelial cell damage. Using the SIMA9 microglia cell line, we found that nitro capsaicin reduced nitric oxide (NO) production in LPS-activated microglia better than its parent compound, capsaicin. Nitro capsaicin also decreased the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhanced the levels of anti-inflammatory factors, IL-4 and IL-10, both at the mRNA and protein levels. In the TNF-α-induced vascular damage model, nitro capsaicin decreased expression and secretion of the proinflammatory cytokines IL-1β and IL-6. Phosphorylated NF-κB p65, a key transcription factor that stimulates the signaling of inflammatory pathways, was also reduced in the presence of nitro capsaicin, suggesting that the anti-inflammatory effects of nitro capsaicin were created through reducing NF-κB activation. Together, we concluded that nitro capsaicin has the potential to be further developed as an anti-neuroinflammatory agent. Full article
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11 pages, 2586 KiB  
Article
Anti-Inflammatory Activity of Panduratin A against LPS-Induced Microglial Activation
by Sopana Jamornwan, Tanida Chokpanuwat, Kwanchanok Uppakara, Sunhapas Soodvilai and Witchuda Saengsawang
Biomedicines 2022, 10(10), 2587; https://doi.org/10.3390/biomedicines10102587 - 15 Oct 2022
Cited by 4 | Viewed by 1985
Abstract
Uncontrolled and excessive microglial activation is known to contribute to inflammation-mediated neurodegeneration. Therefore, reducing neurotoxic microglial activation may serve as a new approach to preventing neurodegeneration. Here, we investigated the anti-inflammatory effects of panduratin A against microglial activation induced by lipopolysaccharides (LPS) in [...] Read more.
Uncontrolled and excessive microglial activation is known to contribute to inflammation-mediated neurodegeneration. Therefore, reducing neurotoxic microglial activation may serve as a new approach to preventing neurodegeneration. Here, we investigated the anti-inflammatory effects of panduratin A against microglial activation induced by lipopolysaccharides (LPS) in the SIMA9 microglial cell line. We initially examined the anti-inflammatory properties of panduratin A by measuring LPS-induced nitric oxide (NO) production and the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Panduratin A significantly reduced NO levels and pro-inflammatory cytokines’ production and secretion. In addition, panduratin A enhanced the production of anti-inflammatory cytokines IL-4 and IL-10. The anti-inflammatory effects of panduratin A are related to the suppression of the NF-κB signaling pathway. Together, these results demonstrate the anti-inflammatory properties of panduratin A against LPS-induced microglial activation, suggesting panduratin A has the potential to be further developed as a new agent for the prevention of neuroinflammation-associated neurodegenerative diseases. Full article
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27 pages, 4674 KiB  
Article
Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity
by Thanasis Rogdakis, Despoina Charou, Alessia Latorrata, Eleni Papadimitriou, Alexandros Tsengenes, Christina Athanasiou, Marianna Papadopoulou, Constantina Chalikiopoulou, Theodora Katsila, Isbaal Ramos, Kyriakos C. Prousis, Rebecca C. Wade, Kyriaki Sidiropoulou, Theodora Calogeropoulou, Achille Gravanis and Ioannis Charalampopoulos
Biomedicines 2022, 10(3), 614; https://doi.org/10.3390/biomedicines10030614 - 6 Mar 2022
Cited by 9 | Viewed by 5036
Abstract
Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent [...] Read more.
Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer’s Disease (AD) progression. However, its low bioavailability and its blood–brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-β actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid β-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer’s Disease, selectively targeting TrkA-mediated pro-survival signals. Full article
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18 pages, 2828 KiB  
Article
Vitisin A, a Resveratrol Tetramer, Improves Scopolamine-Induced Impaired Learning and Memory Functions in Amnesiac ICR Mice
by Lih-Geeng Chen, Ching-Chiung Wang, Yi-Shan Lee, Yi-Yan Sie, Chi-I Chang and Wen-Chi Hou
Biomedicines 2022, 10(2), 273; https://doi.org/10.3390/biomedicines10020273 - 26 Jan 2022
Cited by 8 | Viewed by 3213
Abstract
Resveratrol has been reported to exhibit neuroprotective activities in vitro and in vivo. However, little is known about resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B with the same molecular mass in the improvement of degenerative disorders. In this study, two 95% [...] Read more.
Resveratrol has been reported to exhibit neuroprotective activities in vitro and in vivo. However, little is known about resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B with the same molecular mass in the improvement of degenerative disorders. In this study, two 95% ethanol extracts (95EE) from stem parts of Vitis thunbergii Sieb. & Zucc. (VT-95EE) and from the root (R) parts of Vitis thunbergii var. taiwaniana (VTT-R-95EE) showed comparable acetylcholinesterase (AChE) inhibitory activities. It was found that VT-95EE and VTT-R-95EE showed different distribution patterns of identified resveratrol and resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B based on the analyses of HPLC chromatographic profiles. The hopeaphenol, vitisin A, and vitisin B, showed AChE and monoamine oxidase-B inhibitions in a dose-dependent manner, among which vitisin B and vitisin A exhibited much better activities than those of resveratrol, and had neuroprotective activities against methylglyoxal-induced SH-SY5Y cell deaths. The scopolamine-induced amnesiac ICR mice treated with VT-95EE and its ethyl acetate-partitioned fraction (VT-95EE-EA) at doses of 200 and 400 mg/kg, or vitisin A at a dose of 40 mg/kg, but not vitisin B (40 mg/kg), were shown significantly to improve the impaired learning behaviors by passive avoidance tests compared to those in the control without drug treatments (p < 0.05). Compared to mice in the control group, the brain extracts in the vitisin A-treated mice or donepezil-treated mice showed significant reductions in AChE activities and malondialdehyde levels (p < 0.05), and elevated the reduced protein expressions of brain-derived neurotrophic factor (BDNF) and BDNF receptor, tropomyosin receptor kinase B (TrkB). These results revealed that vitisin A was the active constituent in the VT-95EE and VTT-95EE, and the VT medicinal plant and that the endemic variety of VTT has potential in developing functional foods for an unmet medical need for neurodegenerative disorders. Full article
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36 pages, 895 KiB  
Review
Role of Phytoconstituents as PPAR Agonists: Implications for Neurodegenerative Disorders
by Sanjay, Anshul Sharma and Hae-Jeung Lee
Biomedicines 2021, 9(12), 1914; https://doi.org/10.3390/biomedicines9121914 - 14 Dec 2021
Cited by 17 | Viewed by 5201
Abstract
Peroxisome proliferator-activated receptors (PPAR-γ, PPAR-α, and PPAR-β/δ) are ligand-dependent nuclear receptors that play a critical role in the regulation of hundreds of genes through their activation. Their expression and targeted activation play an important role in the treatment of a variety of diseases, [...] Read more.
Peroxisome proliferator-activated receptors (PPAR-γ, PPAR-α, and PPAR-β/δ) are ligand-dependent nuclear receptors that play a critical role in the regulation of hundreds of genes through their activation. Their expression and targeted activation play an important role in the treatment of a variety of diseases, including neurodegenerative, cardiovascular, diabetes, and cancer. In recent years, several reviews have been published describing the therapeutic potential of PPAR agonists (natural or synthetic) in the disorders listed above; however, no comprehensive report defining the role of naturally derived phytoconstituents as PPAR agonists targeting neurodegenerative diseases has been published. This review will focus on the role of phytoconstituents as PPAR agonists and the relevant preclinical studies and mechanistic insights into their neuroprotective effects. Exemplary research includes flavonoids, fatty acids, cannabinoids, curcumin, genistein, capsaicin, and piperine, all of which have been shown to be PPAR agonists either directly or indirectly. Additionally, a few studies have demonstrated the use of clinical samples in in vitro investigations. The role of the fruit fly Drosophila melanogaster as a potential model for studying neurodegenerative diseases has also been highlighted. Full article
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14 pages, 1058 KiB  
Systematic Review
Efficacy of Acetylcholinesterase Inhibitors on Cognitive Function in Alzheimer’s Disease. Review of Reviews
by Marta Pérez-Gómez Moreta, Natalia Burgos-Alonso, María Torrecilla, José Marco-Contelles and Cristina Bruzos-Cidón
Biomedicines 2021, 9(11), 1689; https://doi.org/10.3390/biomedicines9111689 - 15 Nov 2021
Cited by 52 | Viewed by 4913
Abstract
Alzheimer’s disease (AD) is the most common form of dementia over the age of 65. It is estimated that 115.4 million people will be affected by AD by 2050. Acetylcholinesterase inhibitors (AChEI) are the only available and approved treatment for AD. The aim [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia over the age of 65. It is estimated that 115.4 million people will be affected by AD by 2050. Acetylcholinesterase inhibitors (AChEI) are the only available and approved treatment for AD. The aim of the present study was to analyse the evidence on the efficacy of the AChEI in the treatment of cognitive symptoms of Alzheimer’s disease. For that purpose, a review of review of the systematic reviews (SRs) on this topic was carried out by Web of Science, PubMed, and The Cochrane Library, among others, were searched until 24 September 2021. Thirteen of the 1773 articles evaluated the efficacy of AChEI on cognitive function and/or general condition and/or behavioural disturbances of patients with mild to moderate AD. Methodological quality and risk of bias were rated using the ROBIS scale. The quality of the identified studies was high for nine of them, unclear for two, and finally only in two of the 13 studies did we detect low quality. Overall, AChEI showed very low efficacy in improving cognition in patients with mild to moderate AD. Better results were obtained in improving global state, with donepezil being the most effective treatment. No improvements in behavioural disturbances were found. Few high-quality reviews provide clear evidence of the effects of AChEI on cognition, global change, behaviour, and mortality. The data suggest that AChEI stabilize or slow cognitive deterioration, improving global status. In addition, data indicate that the use of AChEI decreases mortality in patients with mild to moderate AD. However, there is no evidence that they improve patient behaviour. Donepezil is the best therapeutic alternative at a dose of 10 mg/day. Full article
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16 pages, 2267 KiB  
Article
Ladostigil Attenuates Induced Oxidative Stress in Human Neuroblast-like SH-SY5Y Cells
by Keren Zohar, Elyad Lezmi, Tsiona Eliyahu and Michal Linial
Biomedicines 2021, 9(9), 1251; https://doi.org/10.3390/biomedicines9091251 - 17 Sep 2021
Cited by 6 | Viewed by 3289
Abstract
A hallmark of the aging brain is the robust inflammation mediated by microglial activation. Pathophysiology of common neurodegenerative diseases involves oxidative stress and neuroinflammation. Chronic treatment of aging rats by ladostigil, a compound with antioxidant and anti-inflammatory function, prevented microglial activation and learning [...] Read more.
A hallmark of the aging brain is the robust inflammation mediated by microglial activation. Pathophysiology of common neurodegenerative diseases involves oxidative stress and neuroinflammation. Chronic treatment of aging rats by ladostigil, a compound with antioxidant and anti-inflammatory function, prevented microglial activation and learning deficits. In this study, we further investigate the effect of ladostigil on undifferentiated SH-SY5Y cells. We show that SH-SY5Y cells exposed to acute (by H2O2) or chronic oxidative stress (by Sin1, 3-morpholinosydnonimine) induced apoptotic cell death. However, in the presence of ladostigil, the decline in cell viability and the increase of oxidative levels were partially reversed. RNA-seq analysis showed that prolonged oxidation by Sin1 resulted in a simultaneous reduction of the expression level of endoplasmic reticulum (ER) genes that participate in proteostasis. By comparing the differential gene expression profile of Sin1 treated cells to cells incubated with ladostigil before being exposed to Sin1, we observed an over-expression of Clk1 (Cdc2-like kinase 1) which was implicated in psychophysiological stress in mice and Alzheimer’s disease. Ladostigil also suppressed the expression of Ccpg1 (Cell cycle progression 1) and Synj1 (Synaptojanin 1) that are involved in ER-autophagy and endocytic pathways. We postulate that ladostigil alleviated cell damage induced by oxidation. Therefore, under conditions of chronic stress that are observed in the aging brain, ladostigil may block oxidative stress processes and consequently reduce neurotoxicity. Full article
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21 pages, 13282 KiB  
Systematic Review
Can Propolis Be a Useful Adjuvant in Brain and Neurological Disorders and Injuries? A Systematic Scoping Review of the Latest Experimental Evidence
by Felix Zulhendri, Conrad O. Perera and Steven Tandean
Biomedicines 2021, 9(9), 1227; https://doi.org/10.3390/biomedicines9091227 - 15 Sep 2021
Cited by 17 | Viewed by 7386
Abstract
Propolis has been used therapeutically for centuries. In recent years, research has demonstrated its efficacy as a potential raw material for pharmaceuticals and nutraceuticals. The aim of the present scoping review is to examine the latest experimental evidence regarding the potential use of [...] Read more.
Propolis has been used therapeutically for centuries. In recent years, research has demonstrated its efficacy as a potential raw material for pharmaceuticals and nutraceuticals. The aim of the present scoping review is to examine the latest experimental evidence regarding the potential use of propolis in protecting the brain and treating neurological disorders and injuries. A systematic scoping review methodology was implemented. Identification of the research themes and knowledge gap was performed. After applying the exclusion criteria, a total of 66 research publications were identified and retrieved from Scopus, Web of Science, Pubmed, and Google Scholar. Several key themes where propolis is potentially useful were subsequently identified, namely detoxification, neuroinflammation, ischemia/ischemia-reperfusion injury/traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, and epilepsy models, depression, cytotoxicity, cognitive improvement, regenerative medicine, brain infection, and adverse effects. In conclusion, propolis is shown to have protective and therapeutic benefits in alleviating symptoms of brain and neurological disorders and injuries, demonstrated by various in vitro studies, animal models, and human clinical trials. Further clinical research into this area is needed. Full article
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18 pages, 2428 KiB  
Article
Hydrolysable Tannins Exhibit Acetylcholinesterase Inhibitory and Anti-Glycation Activities In Vitro and Learning and Memory Function Improvements in Scopolamine-Induced Amnesiac Mice
by Lih-Geeng Chen, Shyr-Yi Lin, Yi-Shan Lee, Ching-Chiung Wang and Wen-Chi Hou
Biomedicines 2021, 9(8), 1066; https://doi.org/10.3390/biomedicines9081066 - 23 Aug 2021
Cited by 5 | Viewed by 2860
Abstract
Agricultural waste from the hulls of water caltrop (Trapa taiwanesis Nakai, TT-hull) was extracted by either steeping them in cold 95% ethanol (C95E), refluxing 95E, refluxing 50E, or refluxing hot water (HW) to obtain C95EE, 95EE, 50EE, and HWE, respectively. These four [...] Read more.
Agricultural waste from the hulls of water caltrop (Trapa taiwanesis Nakai, TT-hull) was extracted by either steeping them in cold 95% ethanol (C95E), refluxing 95E, refluxing 50E, or refluxing hot water (HW) to obtain C95EE, 95EE, 50EE, and HWE, respectively. These four extracts showed acetylcholinesterase (AChE) inhibitory activities and free radical scavenging activities, as well as anti-non-enzymatic protein glycation in vitro. Eight compounds were isolated from TT-hull-50EE and were used to plot the chromatographic fingerprints of the TT-hull extracts, among which tellimagrandin-I, tellimagrandin-II, and 1,2,3,6-tetra-galloylglucose showed the strongest AChE inhibitory activities, and they also exhibited anti-amyloid β peptide aggregations. The scopolamine-induced amnesiac ICR mice that were fed with TT-hull-50EE or TT-hull-HWE (100 and 200 mg/kg) or tellimagrandin-II (100 and 200 mg/kg) showed improved learning behavior when evaluated using passive avoidance or water maze evaluation, and they showed significant differences (p < 0.05) compared to those in the control group. The enriched hydrolysable tannins of the recycled TT-hull may be developed as functional foods for the treatment of degenerative disorders. Full article
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17 pages, 3259 KiB  
Article
Synthesis and Biological Evaluation of Hydroxylated Monocarbonyl Curcumin Derivatives as Potential Inducers of Neprilysin Activity
by Dimitris Matiadis, See-Ting Ng, Eric H.-L. Chen, Georgia Nigianni, Veroniki P. Vidali, Aleksander Canko, Rita P.-Y. Chen and Marina Sagnou
Biomedicines 2021, 9(8), 955; https://doi.org/10.3390/biomedicines9080955 - 3 Aug 2021
Cited by 9 | Viewed by 2948
Abstract
Background: Alzheimer’s disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Aims: Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and [...] Read more.
Background: Alzheimer’s disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Aims: Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and evaluated for their NEP upregulating potential using sensitive fluorescence-based Aβ digestion and inhibition assays. Results: Compound 4 was the most active one, resulting in a 50% increase in Aβ cleavage activity. Cyclohexanone-bearing derivatives exhibited higher activity enhancement compared to their acetone counterparts. Inhibition experiments with the NEP-specific inhibitor thiorphan resulted in dramatic cleavage reduction. Conclusion: The increased Aβ cleavage activity and the ease of synthesis of 4 renders it an extremely attractive lead compound. Full article
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