scholarly journals Study of 3-(4’-Nitrobenzamido)coumarin using an Alzheimer’s Disease Model

2021 ◽  
Author(s):  
Fernanda Rodríguez-Enríquez ◽  
Dolores Viña ◽  
Eugenio Uriarte ◽  
José Ángel Fontenla ◽  
Maria João Matos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Object Recognition ◽  
Disease Model ◽  
Pharmacokinetic Profile ◽  
Ache Inhibitor ◽  
Mice Model ◽  
Object Recognition Test

Abstract 3-(4’-Nitrobenzamido)coumarin (MJM255), a potent in vitro acetylcholinesterase (AChE) inhibitor, was selected as an in vivo candidate for the discovery of new therapeutic solutions for Alzheimer’s disease. Computational (in silico) studies showing the theoretical physicochemical properties indicate desirable a pharmacokinetic profile for this molecule to cross the blood-brain barrier (BBB). An in vivo study, using the object recognition test (ORT) mice model, was carried out. This compound exhibited a similar effect as eserine, a well-known AChE inhibitor able to cross the BBB.

scholarly journals Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β-Secretase Enzymatic Activity Involved in Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Sayyad Ali ◽  
Muhammad Hassham Hassan Bin Asad ◽  
Fahad Khan ◽  
Ghulam Murtaza ◽  
Albert A. Rizvanov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Evaluation ◽  
Morris Water Maze Test ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Object Recognition Test ◽  
Promising Target

Proteases BACE1 (β-secretases) enzymes have been recognized as a promising target associated with Alzheimer’s disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on virtual screening, thirteen different compounds were synthesized and subsequently evaluated via in vitro and in vivo studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC50=97±0.91 nM) and active to arrest (99%) β-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (p<0.05). Improved pharmacokinetic parameters, viz., Log Po/w (1.76), Log S (-2.73), and better penetration to the brain (BBB permeation) with zero Lipinski violation, made it possible to hit the BACE1 as a potential therapeutic source for AD.

scholarly journals A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing

2021 ◽  
Author(s):  
Sarah Garder ◽  
Catharine Brady ◽  
Cameron Keeton ◽  
Anuj K Yadav ◽  
Sharath C Mallojjala ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Photoacoustic Imaging ◽  
Disease Model ◽  
Photoacoustic Signal ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

<p>In the context of deep-tissue disease biomarker detection and analyte sensing of biologically relevant species, the impact of photoacoustic imaging has been profound. However, most photoacoustic imaging agents to date are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for photoacoustic applications (e.g., high fluorescence quantum yield). Herein, we introduce two effective modifications to the hemicyanine dye to afford PA-HD, a new dye scaffold optimized for photoacoustic probe development. We observed a significant increase in the photoacoustic output, representing an increase in sensitivity of 4.8-fold and a red-shift of the λ<sub>abs</sub> from 690 nm to 745 nm to enable ratiometric imaging. Moreover, to demonstrate the generalizability and utility of our remodeling efforts, we developed three probes using common analyte-responsive triggers for beta-galactosidase activity (PA-HD-Gal), nitroreductase activity (PA-HD-NTR), and hydrogen peroxide (PA-HD-H<sub>2</sub>O<sub>2</sub>). The performance of each probe (responsiveness, selectivity) was evaluated <i>in vitro</i> and <i>in cellulo</i>. To showcase the enhance properties afforded by PA-HD for <i>in vivo</i> photoacoustic imaging, we employed an Alzheimer’s disease model to detect H<sub>2</sub>O<sub>2</sub>. In particular, the photoacoustic signal at 735 nm in the brains of 5xFAD mice (a murine model of Alzheimer’s disease) increased by 1.72 ± 0.20-fold relative to background indicating the presence of oxidative stress, whereas the change in wildtype mice was negligible (1.02 ± 0.14). These results were confirmed via ratiometric calibration which was not possible using the parent HD platform.</p>

scholarly journals A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing

2021 ◽  
Author(s):  
Sarah Garder ◽  
Catharine Brady ◽  
Cameron Keeton ◽  
Anuj K Yadav ◽  
Sharath C Mallojjala ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Photoacoustic Imaging ◽  
Disease Model ◽  
Photoacoustic Signal ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

<p>In the context of deep-tissue disease biomarker detection and analyte sensing of biologically relevant species, the impact of photoacoustic imaging has been profound. However, most photoacoustic imaging agents to date are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for photoacoustic applications (e.g., high fluorescence quantum yield). Herein, we introduce two effective modifications to the hemicyanine dye to afford PA-HD, a new dye scaffold optimized for photoacoustic probe development. We observed a significant increase in the photoacoustic output, representing an increase in sensitivity of 4.8-fold and a red-shift of the λ<sub>abs</sub> from 690 nm to 745 nm to enable ratiometric imaging. Moreover, to demonstrate the generalizability and utility of our remodeling efforts, we developed three probes using common analyte-responsive triggers for beta-galactosidase activity (PA-HD-Gal), nitroreductase activity (PA-HD-NTR), and hydrogen peroxide (PA-HD-H<sub>2</sub>O<sub>2</sub>). The performance of each probe (responsiveness, selectivity) was evaluated <i>in vitro</i> and <i>in cellulo</i>. To showcase the enhance properties afforded by PA-HD for <i>in vivo</i> photoacoustic imaging, we employed an Alzheimer’s disease model to detect H<sub>2</sub>O<sub>2</sub>. In particular, the photoacoustic signal at 735 nm in the brains of 5xFAD mice (a murine model of Alzheimer’s disease) increased by 1.72 ± 0.20-fold relative to background indicating the presence of oxidative stress, whereas the change in wildtype mice was negligible (1.02 ± 0.14). These results were confirmed via ratiometric calibration which was not possible using the parent HD platform.</p>

scholarly journals In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer’s Disease

2021 ◽  
Vol 22 (12) ◽  
pp. 6553
Author(s):  
Sarah Schemmert ◽  
Luana Cristina Camargo ◽  
Dominik Honold ◽  
Ian Gering ◽  
Janine Kutzsche ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Pharmacokinetic Profile ◽  
Rational Drug Design ◽  
Multiple Sources ◽  
Aβ Oligomers ◽  
Rational Drug

Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression of Alzheimer’s disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials. In order to further optimize the compounds and to elucidate the characteristics of therapeutic d-peptides, several rational drug design approaches have been performed. Two of these d-peptides are the linear tandem (head-to-tail) d-peptide RD2D3 and its cyclized form cRD2D3. Tandemization and cyclization should result in an increased in vitro potency and increase pharmacokinetic properties, especially crossing the blood­–brain-barrier. In comparison, cRD2D3 showed a superior pharmacokinetic profile to RD2D3. This fact suggests that higher efficacy can be achieved in vivo at equally administered concentrations. To prove this hypothesis, we first established the in vitro profile of both d-peptides here. Subsequently, we performed an intraperitoneal treatment study. This study failed to provide evidence that cRD2D3 is superior to RD2D3 in vivo as in some tests cRD2D3 failed to show equal or higher efficacy.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System

2019 ◽  
Vol 20 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Chi Zhang ◽  
Zhichun Gu ◽  
Long Shen ◽  
Xianyan Liu ◽  
Houwen Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Outcome ◽  
Neuroprotective Effect ◽  
Sirna Delivery ◽  
Repeated Administration ◽  
Spatial Learning And Memory ◽  
In Vivo Evaluation

Background: To deliver drugs to treat Alzheimer’s Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons. Methods: Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant. Results and Conclusion: After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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