Discovery of novel β-carboline derivatives as selective AChE inhibitors with GSK-3β inhibitory property for the treatment of Alzheimer's disease

2021 ◽  
pp. 114095
Author(s):  
Wenwu Liu ◽  
Xin Liu ◽  
Wenjie Liu ◽  
Yaping Gao ◽  
Limeng Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Property ◽  
Ache Inhibitors ◽  
Gsk 3Β

Virtual Screening in Chinese Herbs with Multi-Target Effect on Alzheimer's Disease

2013 ◽  
Vol 765-767 ◽  
pp. 256-260
Author(s):  
Yan Ling Zhang ◽  
Yuan Ming Wang ◽  
Yan Jiang Qiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Glycogen Synthase ◽  
Chinese Herbs ◽  
Multiple Targets ◽  
Active Compounds ◽  
Ache Inhibitors ◽  
Gsk 3Β ◽  
Pharmacophore Models

Multiple targets which closely related to Alzheimer's disease (AD) pathogenesis were selected for pharmacophore models generation and virtual screening in Chinese herbs. The targets comprised Acetylcholinesterase (AchE), muscarinic receptor 1 (M1), γ-secretase and glycogen synthase kinase 3β (GSK-3β). The pharmacophore models, which of AchE inhibitors, M1 agonists, γ-secretase inhibitors and GSK-3β inhibitors, were constructed by distance comparison method. Four testing databases for the evaluation of pharmacophore models were constructed with the active compounds with clearly marked activity on each target. The metric CAI (Comprehensive Appraisal Index) was then used to evaluate and obtain the best pharmacophore models of each target, which were then applied to screen the Traditional Chinese Medicine Database for potential active compounds in Chinese herbs. Four common used herbs were obtained, which contain the active compounds and can act on multiple targets, and were expected to have multiple activity of anti-AD disease.

scholarly journals Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer’s Disease Drug Discovery

2018 ◽  
Vol 9 (3) ◽  
pp. 171-176 ◽  
Author(s):  
Xue-Yang Jiang ◽  
Ting-Kai Chen ◽  
Jun-Ting Zhou ◽  
Si-Yu He ◽  
Hong-Yu Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Ache Inhibitors ◽  
New Strategy ◽  
Gsk 3Β

Polycyclic maleimide-based derivatives as first dual modulators of neuronal calcium channels and GSK-3β for Alzheimer's disease treatment

2019 ◽  
Vol 163 ◽  
pp. 394-402 ◽  
Author(s):  
Alessandra Bisi ◽  
Raquel L. Arribas ◽  
Matteo Micucci ◽  
Roberta Budriesi ◽  
Alessandra Feoli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Calcium Channels ◽  
Disease Treatment ◽  
Gsk 3Β ◽  
Neuronal Calcium Channels

The ABC of Alzheimer's Disease: Behavioral Symptoms and Their Treatment

2002 ◽  
Vol 14 (S1) ◽  
pp. 27-49 ◽  
Author(s):  
George T. Grossberg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Options ◽  
Lewy Body Dementia ◽  
Economic Cost ◽  
Brain Regions ◽  
Behavioral Symptoms ◽  
Psychotic Symptoms ◽  
Ache Inhibitors ◽  
Che Inhibitors

Behavioral and psychological symptoms of dementia (BPSD) are a common manifestation of Alzheimer's disease (AD) and other dementia syndromes. Patients experience prominent and multiple symptoms, which are both distressing and a source of considerable social, health, and economic cost. Development of symptoms is in part related to progressive neurodegeneration and cholinergic deficiency in brain regions important in the regulation of behavioral and emotional responses including the cortex, hippocampus, and limbic system. Cholinesterase (ChE) inhibitors offer a mechanism-based approach to therapy to enhance endogenous cholinergic neurotransmission. Studies using ChE inhibitors have demonstrated their clear potential to improve or stabilize existing BPSD. Differences have been noted between selective acetylcholinesterase (AChE) inhibitors (donepezil and galantamine) and dual ChE inhibitors (rivastigmine) in terms of treatment response. While donepezil has shown efficacy in moderate to severe noninstitutionalized AD patients, conflicting results have been obtained in mild to moderate patients and in nursing home patients. Galantamine has been shown to delay the onset of BPSD during a five-month study but has been otherwise poorly studied to-date. Both donepezil and galantamine have not as yet demonstrated efficacy in reducing psychotic symptoms or in reducing levels of concomitant psychotropic medication use. Studies with the dual ChE inhibitor rivastigmine in mild to moderately severe AD and in Lewy body dementia (LBD) have shown improvements in behavioral symptoms including psychosis. Improvements have been maintained over a period of up to two years. In addition, institutionalized patients with severe AD have shown symptomatic benefits with a reduction in the requirement for additional psychotropic drugs following treatment with rivastigmine. The psychotropic properties associated with rivastigmine may in part be mediated through effects on butyrylcholinesterase. Current treatment options are limited for patients with dementia syndromes other than AD. However, data concerning rivastigmine in patients with LBD and preliminary studies in Parkinson's disease dementia and vascular dementia suggest a role for ChE inhibitors across the spectrum of dementia syndromes. Finally, studies that incorporated a delayed start design demonstrate that ChE inhibitors may delay the progression of BPSD.

scholarly journals Influence of Acetylcholinesterase Inhibitors Used in Alzheimer’s Disease Treatment on the Activity of Antioxidant Enzymes and the Concentration of Glutathione in THP-1 Macrophages under Fluoride-Induced Oxidative Stress

2018 ◽  
Vol 16 (1) ◽  
pp. 10 ◽  
Author(s):  
Marta Goschorska ◽  
Izabela Gutowska ◽  
Irena Baranowska-Bosiacka ◽  
Katarzyna Piotrowska ◽  
Emilia Metryka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Antioxidant Enzymes ◽  
Antioxidant Properties ◽  
Reactive Oxygen ◽  
Acetylcholinesterase Inhibitors ◽  
Oxygen Species ◽  
Ache Inhibitors

It has been reported that donepezil and rivastigmine, the acetylcholinesterase (AchE) inhibitors commonly used in the treatment of Alzheimer’s disease (AD), do not only inhibit AChE but also have antioxidant properties. As oxidative stress is involved in AD pathogenesis, in our study we attempted to examine the influence of donepezil and rivastigmine on the activity of antioxidant enzymes and glutathione concentration in macrophages—an important source of reactive oxygen species and crucial for oxidative stress progression. The macrophages were exposed to sodium fluoride induced oxidative stress. The antioxidant enzymes activity and concentration of glutathione were measured spectrophotometrically. The generation of reactive oxygen species was visualized by confocal microscopy. The results of our study showed that donepezil and rivastigmine had a stimulating effect on catalase activity. However, when exposed to fluoride-induced oxidative stress, the drugs reduced the activity of some antioxidant enzymes (Cat, SOD, GR). These observations suggest that the fluoride-induced oxidative stress may suppress the antioxidant action of AChE inhibitors. Our results may have significance in the clinical practice of treatment of AD and other dementia diseases.

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