Nigella sativa Oil Preserved Anxiety-Like, Motor and Memory Related Behaviours and Neuronal Integrity in Dichlorvos Induced Acetyl Cholinesterase Inhibitions in Rats

Organophosphates are irreversible cholinesterase (ChE) inhibitors with neurological consequences, and there is not yet an effective antidote. Here, we investigated the effects of Nigella sativa oil (NSO) on the ChE inhibition, neurobehavioural and histopathological changes following dichlorvos (DDVP) ingestions in rats. Thirty-two male Wistar rats were randomised into four groups, receiving 1 ml/kg of normal saline, 8.8 mg/kg of DDVP, 8.8 mg/kg of DDVP and 1 ml/kg of NSO, and 1 ml/kg of NSO only respectively, for 14 consecutive days. Locomotor, anxiety-like behaviours and spatial working memory were assessed on the 14th day, using open field (OF), Y-maze and modified elevated plus maze paradigms. The rats were euthanized on the 15th day and the brains excised; three brains were fixed for histopathology, and the other five prepared for biochemical analysis of acetyl cholinesterase (AChE). DDVP exposure caused significant reductions in frontal, amygdala and cerebella AChE activity, spontaneous alternations, line crossing and rearing frequencies and time in centre square, and caused increase in freezing period, transfer latency and necrotic-like cells. NSO intervention was able to reverse DDVP effects on AChE activities, explorative, locomotor, anxiety and spatial memory behaviours in co-exposed rats. It also preserved the histological integrity of the investigated brain regions. It can be concluded that NSO, may be potent against organophosphates induced neurotoxicity and their neurobehavioural consequences through the modulation of AChE activities.

Cholinesterase Inhibitory Potential of Quercetin towards Alzheimer’s Disease - A Promising Natural Molecule or Fashion of the Day? – A Narrowed Review

: Natural substances are known to have strong protective effects against neurodegenerative diseases. Among them, phenolic compounds, especially flavonoids, come to the fore with their neuroprotective effects. Since quercetin, which is found in many medicinal plants and foods, is also taken through diet, its physiological effects on humans are imperative. Many studies have been published up to date on the neuroprotective properties of quercetin, a flavanol derivative. However, there is no review published so far summarizing the effect of quercetin on the cholinesterase (ChE) enzymes related to the cholinergic hypothesis, which is one of the pathological mechanisms of Alzheimer's disease (AD). However, ChE inhibitors regardless of natural or synthetic play a vital role in the treatment of AD. Although the number of studies on the ChE inhibitory effect of quercetin is limited, it deserves to be discussed in a review article. With this sensitivity, the neuroprotective effect of quercetin against AD through ChE inhibition was scrutinized in the current review study. In addition, studies on the bioavailability of quercetin and its capacity to cross the blood-brain barrier and how this capacity and bioavailability can be increased were given. Generally, studies containing data published in recent years were obtained from search engines such as PubMed, Scopus, and Medline and included herein. Consequently, quercetin should not be considered as a fashionable natural compound and should be identified as a promising compound, especially with increased bioavailability, for the treatment of AD.

Activity-guided purification reveals quercetin as the most efficient cholinesterase inhibitor in wild strawberry (Fragaria vesca L.) and apricot (Prunus armeniaca L.) fruit extract

Cholinesterase (ChE) inhibitors are commonly approved for the Alzheimer’s disease therapy which should restore the original levels of acetylcholine in the brain. In this work, a suitable purification procedure of ChE inhibitors from wild strawberry (Fragaria vesca L.) and apricot (Prunus armeniaca L.) fruit is presented. Activity-guided purification was based on ultrafiltration (0.2 µm → 5 kDa → 3 kDa) of water extract from fruit followed by preparative chromatography (Sephadex LH-20 and HPLC-C18) and analytical HPLC-C18. At every stage of purification, anti-ChE activity was measured in each fraction using Ellman’s colorimetric method. The most active ChE inhibitor purified from both fruits was quercetin and the chemical structure was confirmed by infrared (IR) and proton nuclear magnetic resonance (1H-NMR) spectroscopies. The fast purification procedure can be used for isolating phenolic ChE inhibitors from other fruits from the Rosaceae family.

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones

Background: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer’s disease (AD). Methods: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated. Results: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively. Conclusion: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

Synthesis and Biological Evaluation of New Cholinesterase Inhibitors for Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD.

Discovery of new acetylcholinesterase and butyrylcholinesterase inhibitors through structure-based virtual screening

Small molecule cholinesterase (ChE) inhibitors represent one of the most effective therapeutic strategies for the treatment of Alzheimer's disease (AD).

Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer’s Disease: A Review of Clinical Trials

Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer’s disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage.Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD.Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012.Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.

What Is the Rationale for New Treatment Strategies in Alzheimer's Disease?

Alzheimer's disease (AD) is characterized by the abnormal extracellular accumulation of amyloid β-peptide (Aβ) into neuritic plaques and the intraneuronal aggregation of the microtubule-associated protein tau to form neurofibrillary tangles. These molecular events are implicated in the selective damage to neural systems critical for the brain functions that are impaired in AD. Impairment of cholinergic neurotransmission may be an important factor underlying the defects in cognition and memory that characterize AD. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, cause symptomatic improvement by inhibiting the breakdown of the neurotransmitter acetylcholine to increase its synaptic availability and, in the case of galantamine, by also allosterically potentiating nicotinic cholinergic receptors. Other agents, including vitamin E, monoamine oxidase inhibitors, and statins, have shown some benefit in epidemiological studies and clinical trials although compelling evidence of their efficacy is lacking. Memantine, shown to cause cognitive and functional improvement, is not an ChE inhibitor and does not interact with marketed ChE inhibitors. While the mechanism of action of memantine in AD is not known, the principal pharmacologic actions at therapeutic dose are inhibition of ionotropic neurotransmitter receptors, specifically N-methyl-D-aspartate (NMDA), 5-HT3, and nicotinic receptors. Like other NMDA antagonists, memantine causes behavioral activation associated with enhanced cerebral glucose utilization. Studies have shown that memantine can reverse the decreased metabolic activity associated with AD, possibly accounting for its beneficial effects on cognition and global functioning. Memantine also has neuroprotective properties and can inhibit Aβ-induced neurodegeneration.

Fatal Aspiration Pneumonia during Transition from Donepezil to Rivastigmine

OBJECTIVE: To report a case of fatal aspiration pneumonia in a patient shortly after initiation of rivastigmine and discontinuation of donepezil, with no washout period between therapies. CASE SUMMARY: An 83-year-old white man presented to the emergency department in respiratory distress (O2 saturation 70%; RR 44 breaths/min) secondary to aspiration. He had started rivastigmine 1.5 mg twice daily that same day. The patient had been previously treated with donepezil 10 mg/d, and there was no washout period. He was intubated due to worsening respiratory status and was transferred to the cardiac care unit. He then became hypotensive and required dopamine and fluid support. Brief bronchoscopy revealed food particles in the lower airways and bile-stained secretions. Intubation was notable for the large amount of secretions. The patient died approximately 27 hours after presentation to the emergency department. Blood and sputum cultures were subsequently positive for Haemophilus influenzae. DISCUSSION: Cholinesterase (ChE) inhibitors approved for treatment of Alzheimer disease are associated with nausea and vomiting in a sizable percentage of patients, ranging from 5% to 31% in clinical trials. Most of these adverse events occur during the initiation/titration phase of therapy. An additive risk of adverse events may be expected with coadministration of ChE inhibitors or cholinergic agents or, potentially, with an inadequate washout period between such agents. Review of MEDLINE (1966–July 2002) and International Pharmaceutical Abstracts (1970–July 2002) failed to identify any previous reports of aspiration with rivastigmine or donepezil. CONCLUSIONS: A washout period should be considered when switching between ChE inhibitors to minimize the risk of vomiting and aspiration.

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

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.