Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and their molecular docking simulation.

A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-b]quinoxaline heterocyclic hybrids 7a-j were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomethine ylide employed is first of its kind and generated in situ from indenoquinoxalinone and l-tryptophan, a combination that has not been employed previously for the in situ generation of azomethine ylides. The synthesized heterocyclic hybrids 7a-j were evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 7h and 7j displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC50 values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.

Willughbeia cochinchinensis prevents scopolamine-induced deficits in memory, spatial learning, and object recognition in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Willughbeia cochinchinensis (WC) has been used in Vietnamese traditional medicine for the treatment of dementia as well as diarrhea, heartburn, and cutaneous abscess and as a diuretic. AIM: Alzheimer's disease (AD) is one of the most prevalent diseases in elderly individuals. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors have been widely used to treat patients with AD. In the present study, we investigated anti-AChE and anti-BChE activities of a natural product, WC, for its potential applications in therapies to prevent/treat dementia. MATERIALS AND METHODS: First, compounds extracted from WC were tested for their AChE and BChE inhibitory activities in vitro. Second, in vivo behavioral experiments were performed to investigate the effects of WC at doses of 100, 150, and 200mg/kg on scopolamine (1.5mg/kg)-induced memory and cognitive deficits in mice. The behavior of mice treated with and without WC and/or scopolamine was tested using the Y-maze, Morris water maze, and novel object recognition task. RESULTS: The results of the in vitro assay demonstrated anti-AChE and anti-BChE activities of the compounds extracted from WC. The results of behavioral experiments showed that the administration of WC prevented 1) scopolamine-induced decrease in spontaneous alternation (%) behavior in the Y-maze, 2) scopolamine-induced deficits in spatial learning and memory in the Morris water maze, and 3) scopolamine-induced deficits in novel object recognition. These results indicate that WC prevents cognitive and memory deficits induced by scopolamine injection. CONCLUSIONS: Our findings suggest that WC may represent a novel candidate for the treatment of memory and cognitive deficits in humans with dementia.

Activity and polymorphisms of butyrylcholinesterase in a Polish population.

Butyrylcholinesterase (BChE) activity assay and inhibitor phenotyping can help to identify individuals at risk of prolonged paralysis following the administration of neuromuscular blocking agents, like succinylcholine, pesticides and nerve agents. In this study, the activity of BChE and its sensitivity to inhibition by dibucaine and fluoride was evaluated in 1200 Polish healthy individuals. In addition, molecular analysis of all exons, exon-intron boundaries and the 3'UTR sequence of the BCHE gene was performed in a group of 72 subjects with abnormal BChE activity (<2000 U/L and >5745 U/L) or with DN (Dibucaine Number) or FN (Fluoride-Number) values outside the reference range (DN < 78 and FN < lower than wild type). In a studied group, BChE activity range was similar to those observed in other populations. BChE activity screening allowed to detect UA and UF phenotypes in 26 (2.2%) and 15 (1.2%) individuals, respectively. Observed UA or UF phenotypes were confirmed by direct sequencing and heterozygous c.293A > G or c.1253G > T substitutions were identified in all cases. Nine out of 18 (50%) individuals with BChE activity below 2000 U/L had a mutation in 5'UTR (32G/A), intron 2 (c.1518-121T/C) or exon 4 (c.1699G/A; the K variant mutation). Majority of the individuals with BChE activity ≥6000 U/L were wild type. To summarize, the range of BChE activity in a Polish population is similar to those observed in other countries. We conclude that the BChE phenotyping assay is a reliable method for identification of individuals with the UA and UF genotypes.

Atividade da butirilcolinesterase e fatores de risco cardiovascular em adolescentes obesos submetidos a um programa de exercícios físicos / Butyrylcholinesterase activity and cardiovascular risk factors in obese adolescents submitted to an exercise program

OBJETIVO: Avaliar o efeito de 12 semanas de exercícios físicos em variáveis associadas a fatores de risco cardiovascular e na atividade da butirilcolinesterase (BChE) em adolescentes obesos. SUJEITOS E MÉTODOS: A amostra foi composta por 24 obesos e 51 eutróficos controles. Inicialmente e após 12 semanas foram avaliados: peso, estatura, IMC, circunferência abdominal (CA), percentual de gordura (%G), consumo máximo de oxigênio (VO2máx), pressão arterial sistólica (PAS) e diastólica (PAD), glicemia (GLI) e insulinemia (INS) basal e após 120 min, triacilglicerol (TG), colesterol total (CT), colesterol LDL, colesterol HDL e a atividade da BChE (kU/l). RESULTADOS: Após a intervenção, houve redução significativa no IMC, CA, %G, PAD, PAD, TG, GLI 120, INS, INS 120 min e na atividade da BChE. CONCLUSÃO: A redução da atividade da BChE, observada após a intervenção, foi acompanhada da redução de variáveis associadas a risco cardiovascular e à obesidade, indicando que a BChE pode ser utilizada como marcador secundário para os riscos associados à obesidade precoce.

OBJECTIVE: To evaluate the effect of 12 weeks of physical exercise (PE) on cardiovascular risk factors and BChE activity in obese adolescents. SUBJECTS AND METHODS: The sample consisted of 24 obese adolescents and 51 normal weight controls. The following variables were measured in the initial stage and after 12 weeks: weight, height, BMI, waist circumference (WC), fat percentage (% F), maximal oxygen uptake (VO2max), systolic (SBP) and diastolic (DBP) blood pressure, glucose (GLY) and insulin (INS) at baseline and after 120 min, triacylglycerol (TG), total cholesterol (TC), LDL cholesterol, HDL cholesterol, and BChE activity (kU/l). RESULTS: After the intervention, there was significant reduction in BMI, WC, %F, TG, GLI 120, INS 120 min, and BChE activity. CONCLUSION: The reduction in BChE activity, observed after physical exercise, was accompanied by the reduction of the variables associated with cardiovascular risk and obesity, indicating that BChE can be used as a secondary marker for the risk associated with early onset obesity.

1914G variant of BCHE gene associated with enzyme activity, obesity and triglyceride levels.

Polymorphisms of butyrylcholinesterase (BChE) have been reported to be associated to weight, BMI variance and hypertriglyceridemia in adults and adolescents. The aim of the present study was to investigate the association of -116A (SNP: G/A; rs1126680) and 1914G (SNP: A/G; rs3495) variants of BCHE gene with anthropometric and biochemical variables associated with obesity in population sample of 115 individuals, from Southern Brazil. Participants were grouped in two categories: obese (BMI≥30) and non-obese (BMI<30). The 1914G allele showed significantly higher frequency in the obese group, and carriers of 1914G allele showed lower mean BChE activity when compared to 1914A carriers (p=0.006). Higher means of BMI (p=0.02) and triglyceride (TG; p=0.01) were found in 1914G carriers (BMI=27.57 kg/m(2); TG=150.8 mg/dL) when compared to 1914A homozygotes (BMI=25.55 kg/m(2); TG=107.9 mg/dL). Carriers of the -116A allele showed lower mean BChE activity than usual homozygotes, and the -116A variant was found in cis with 1914G (p<0.0001; D'=1). The region of BCHE gene that contains the 1914G mutation site is target of microRNAs (miRs) and the response of BChE to glucocorticoids is especially influenced by these miRs. Therefore, it is possible that the 1914G allele can be interfering in gluconeogenesis, hyperglycemia, lipolysis and body fat distribution. This lower activity may cause an imbalance in lipid metabolism, which may lead to an increased predisposition to obesity and to a lower ability to maintain metabolic homeostasis.

Effects of physical exercise on butyrylcholinesterase in obese adolescents.

The aim of the present study was to evaluate the effect of a 12 week program of physical exercise (PE) on butyrylcholinesterase (BChE) in obese adolescents. This study compared obese adolescents (N = 54) before and after PE, regarding the relative intensity (RI) and activity of different molecular forms (G1, G2, G4 and G1-ALB) of BChE found in plasma. Waist circumference (WC) and lipid profile were also assessed before and after PE. It was shown that before PE, mean plasma BChE activity was significantly higher in obese than in non-obese adolescents and that it was significantly reduced after PE, becoming similar to that found in non-obese adolescents. Lipid profile and WC also changed in response to PE. These results are consistent with studies that found a correlation between BChE and lipid metabolism and suggest that PE may have led to a physiological regularization of plasma BChE activity. Although mean BChE activity of each isoform was significantly reduced by PE, their RI did not change. This is in accordance with a previous suggestion that this proportion is maintained under factors such as obesity, and may therefore be important for BChE functions.