Flavanone Glycosides as Acetylcholinesterase Inhibitors: Computational and Experimental Evidence

Acetylcholinesterase hydrolyzes the neurotransmitter called acetylcholine and is crucially involved in the regulation of neurotransmission. One of the observable facts in the neurodegenerative disorders like Alzheimer''s disease is the decrease in the level of acetylcholine. Available drugs that are used for the treatment of Alzheimer''s disease are primarily acetylcholinesterase inhibitors with multiple activities. They maintain the level of acetylcholine in the brain by inhibiting the acetylcholinesterase function. Hence acetylcholinesterase inhibitors can be used as lead compounds for the development of drugs against AD. In the present study, the binding potential of four flavanone glycosides such as naringin, hesperidin, poncirin and sakuranin against acetylcholinesterase was analysed by using the method of molecular modeling and docking. The activity of the top scored compound, naringin was further investigated by enzyme inhibition studies and its inhibitory concentration (IC₅₀) towards acetylcholinesterase was also determined.     

Synthesis and biological evaluation of tacrine-thiadiazolidinone hybrids as dual acetylcholinesterase inhibitors

The synthesis of tacrine-thiadiazolidinone hybrids is described. These compounds are designed as dual acetylcholinesterase inhibitors binding simultaneously to the peripheral and catalytic sites of the enzyme. All tested compounds exhibit significant AChE inhibitory activity. Competition assays using propidium as reference of selective ligand for the peripheral anionic site on acetylcholinesterase indicates the influence of the designed compounds over the peripheral site. They can be considered as new leads in the optimization of Alzheimer's disease modifying agents.     

Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease

Alzheimer''s disease (AD) is a neurodegenerative disorder characterized clinically by cognitive impairments that progress to dementia and death. The earliest symptoms of AD present as a relatively pure deficit in memory retrieval. Therefore, drug treatments that intervene in the early stages of AD by rescuing memory deficits could be promising therapies to slow, or even reverse progression of the disease. In this study, we tested the potential of systemic histone deacetylase inhibitor (HDACi) treatment to rescue cognitive deficits in a mouse model of AD. APPswe/PS1dE9 mice showed pronounced contextual memory impairments beginning at 6 months of age. Chronic HDACi injections (2–3 weeks) did not alter contextual memory formation in normal mice, but had profound effects in transgenic animals. Injections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinza®) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated transgenic mice showed that the newly consolidated memories were stably maintained over a 2-week period. Measurement of the HDAC isoform selectivity profile of sodium valproate, sodium butyrate, and vorinostat revealed the common inhibition of class I HDACs (HDAC1, 2, 3, 8) with little effect on the class IIa HDAC family members (HDAC4, 5, 7, 9) and inhibition of HDAC6 only by vorinostat. These preclinical results indicate that targeted inhibition of class I HDAC isoforms is a promising avenue for treating the cognitive deficits associated with early stage AD.     

Clinical experience of galantamine in dementia: a series of case reports

SUMMARY

Objective: To use case studies to add the benefit of personal experience with galantamine to published literature and to demonstrate the type of patients that may benefit from this treatment.

Methods: We describe eleven patients, aged 57–90 years, fulfilling the consensus diagnostic criteria for probable Alzheimer's disease, mixed dementia, vascular dementia, Lewy body dementia or Parkinson's dementia. All patients were treated with galantamine that may enhance cholinergic function in the brain by inhibiting acetylcholinesterase and potentiating the effects of acetylcholine at nicotinic acetylcholine receptors. Clinical features were rated according to eight assessment scales in old age psychiatry and additional information was obtained from family and other carers. In some cases caregiver distress was measured.

Results: All patients described showed a general improvement in cognition and neuropsychiatric symptoms, although observed improvements and effects were not always reflected by the results of formal assessments. Several patients became more independent, particularly in their activities of daily living, and treatment was felt to have helped maintain independence in their home environment, either alone or with their family or carers. One man continued in employment. Adverse events included nausea and vomiting.

Conclusions: Outcomes in this case series indicate that galantamine is well tolerated and highlight aspects of the different side-effect profiles of the anticholinesterase inhibitors. Subjective benefits were not always apparent from objective measures. These case studies demonstrate the type of patients that may benefit from galantamine.     

Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer

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乙酰胆碱酯酶抑制剂的构效关系研究

综述用于治疗阿尔茨海默病(AD)的乙酰胆碱酯酶抑制剂的构效关系，为开发新一代治疗老年痴呆症的药物提供理论依据。乙酰胆碱酯酶抑制剂作为治疗AD的一线药物疗效确切，是现阶段对AD病人最有效的治疗手段。     

Effect of rivastigmine in the treatment of behavioral disturbances associated with dementia: review of neuropsychiatric impairment in Alzheimer's disease

ABSTRACT

Cognitive decline is conventionally regarded as the defining clinical symptom of Alzheimer's disease (AD), but behavioral and neuropsychiatric symptoms are also present throughout the course of the disease. In fact, behavioral symptoms may appear before cognitive decline is diagnosed. The presence of these symptoms may predict an increasing need for community-based services or even nursing home placement. The characteristic behavioral and neuropsychiatric symptoms associated with AD may be related to the same pathophysiology that underlies the cognitive abnormalities. AD is characterized by a loss of cholinergic neurons as well as by the presence of neurofibrillary tangles (NFTs) and senile plaques in brain regions with cholinergic deficits, resulting in a deficiency in acetylcholine (ACh) in areas of the brain that modulate cognition, behavior, and emotion. Cholinesterase inhibitors are thought to augment or maximize the concentration of ACh in the synaptic cleft. Rivastigmine is a dual inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), enzymes involved in hydrolysis of ACh. Literature searches using MEDLINE and EMBASE databases were performed to identify studies of rivastigmine (through August 2005) that assessed neuropsychiatric aspects of AD. Rivastigmine has been demonstrated to be safe and effective in stabilizing or improving the cognitive symptoms of AD in 3 large, well-controlled, randomized clinical trials, which also demonstrated that rivastigmine improves overall global functioning. Smaller studies and meta-analyses of pooled data from the 3 large trials have suggested that rivastigmine may improve the behavioral and neuropsychiatric symptoms associated with AD.     

An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available.

Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders.

What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases.

Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.     

Cholinesterase inhibition: is there evidence for disease-modifying effects?

Abstract

Background:

Cholinesterase inhibitors are broadly established as first-line symptomatic therapy for Alzheimer's disease (AD). Symptomatic effects are mediated by the inhibition of acetyl- and/or butyryl-cholinesterase (AChE and/or BuChE) – the enzymes that degrade acetylcholine (ACh) in the synapse. However, ACh is also found outside the synapse (‘extracellular ACh’) where, among other activities, it plays a role in controlling inflammation and might impact on pathological changes.     

An update on the pharmacology of galantamine

Alzheimer's disease (AD) is associated with a gradual loss of attention and memory that has been related to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons. The first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibition of acetylcholinesterase. The acetylcholinesterase inhibitors used to treat AD patients at present are donepezil, rivastigmine and galantamine. This review summarises the current state of the art concerning the pharmacology of galantamine, focusing on the most important details of its possibilities as an acetylcholinesterase inhibitor, an allosteric potentiator of neuronal nicotinic receptors for acetylcholine, a modulator of neurotransmitter release, and an agent causing neuroprotection through an antiapoptotic action. In so doing, galantamine will be discussed in the context of the treatment of dementia, both of AD type and of mixed vascular-Alzheimer type.     

A New Therapeutic Target in Alzheimer's Disease Treatment: Attention to Butyrylcholinesterase

Summary

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly, characterised by widespread loss central cholinergic function. The only symptomatic treatment proven effective, to date is the use of cholinesterase (ChE) inhibitors to augment surviving cholinergic activity. ChE inhibitors act on the enzymes that hydrolyse acetylcholine (ACh) following synaptic release. In the healthy brain, acetylcholinesterase (AChE) predominates (80%) and butyrylcholinesterase (BuChE) is considered to play a minor role in regulating brain ACh levels. In the AD brain, BuChE activity rises while AChE activity remains unchanged or declines. Therefore both enzymes are likely to have involvement in regulating ACh levels and represent legitimate therapeutic targets to ameliorate the cholinergic deficit. The two enzymes differ in location, substrate specificity and kinetics. Recent evidence suggests that BuChE may also have a role in the aetiology and progression of AD beyond regulation of synaptic ACh levels. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine, MF-8622) and ChE inhibitors such as rivastigmine, which have a dual inhibitory action on both AChE and BuChE, indicate potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. The development of specific BuChE inhibitors and the continued use of ChE inhibitors with the ability to inhibit BuChE in addition to AChE should lead to improved clinical outcomes.