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1.
J Ethnopharmacol ; 318(Pt A): 116792, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37356745

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fufangmuniziqi formula (FFMN), a traditional Uyghur medicine used in China, is derived from an ancient Uyghur medical book and consists of 13 herbs. The herbs of FFMN, such as Peganum harmala L., Glycyrrhiza uralensis Fisch., and Nigella glandulifera, have been demonstrated to have acetylcholinesterase (AChE) inhibitory, anti-neuroinflammatory, or antioxidant effects. Therefore, FFMN may have a good anti-Alzheimer's disease (AD) effect, but its specific action and mechanism need to be further proven. AIM OF THE STUDY: This study aims to investigate the anti-AD effects of FFMN and the role played by alkaloids, flavonoids, and saponins in anti-AD. MATERIALS AND METHODS: The alkaloids, flavonoids, and saponins fractions of FFMN were prepared by macroporous resin chromatography. The absorbed ingredients in the drug-containing serum were identified by UPLC⁃Q⁃TOF⁃MS. An AD mouse model was established by intraperitoneal injection of scopolamine (SCO). The role of different fractions of FFMN in the anti-AD process was examined by Morris water maze (MWM), in-vitro cell, and AChE inhibition assay. RESULTS: A total of 20 ingredients were identified in the serum samples collected after oral administration of FFMN, and seven compounds were selected as candidate active compounds. MWM experiments showed that different fractions of FFMN could significantly improve SCO-induced learning memory impairment in mice. The alkaloids fraction (ALK) regulated cholinergic function by inhibiting AChE activity, activating choline acetyltransferase activity, and protein expression. Flavonoids and saponins were more potent than the ALK in downregulating pro-inflammatory factors or inflammatory mediators, such as TNF-α, MPO, and nitric oxide. Western blot results further confirmed that flavonoids and saponins attenuated neuroinflammation by inhibiting the phosphorylation of IκB and NF-κB p65. This result was also verified by in-vitro cellular assays. FFMN enhanced antioxidant defense by increasing the activity of superoxide dismutase and reducing the production of MDA. Combined with cellular experiments, flavonoids and saponins were proven more protective against oxidative damage. CONCLUSION: FFMN improved cognitive and memory impairment in the SCO-induced AD mouse model. ALK mainly enhanced the function of the cholinergic system. Flavonoid and saponin fractions mainly attenuated neuroinflammation and oxidative stress by modulating the NF-κB pathway. All these findings strongly suggested that the combination of alkaloid, flavonoid, and saponin fractions derived from FFMN is a promising anti-AD agent that deserves further development.


Assuntos
Alcaloides , Disfunção Cognitiva , Saponinas , Camundongos , Animais , Escopolamina/farmacologia , Acetilcolinesterase/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , Alcaloides/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Antioxidantes/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Estresse Oxidativo , Colinérgicos/farmacologia , Receptores Proteína Tirosina Quinases/efeitos adversos , Receptores Proteína Tirosina Quinases/metabolismo , Aprendizagem em Labirinto
2.
J Ethnopharmacol ; 318(Pt A): 116911, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37451488

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional system of medicine, Piper species, or its components are widely used to treat many diseases including memory improvement. One of the wild species Piper trioicum Roxb. (Piperaceae) is found in South Asian countries. The whole plant is used as folk medicine to improve memory. AIM OF THE STUDY: To our knowledge, no previous research has investigated the neuroprotective activities of P. trioicum. So, we studied the ameliorative effect of P. trioicum in attenuating cognitive deficit in scopolamine induced neurotoxicity in experimental rats. MATERIALS AND METHODS: Wistar rats were exposed to scopolamine (3 mg/kg, i. p.) for 14 consecutive days, and the effect of P. trioicum (HAPT; oral, 300, 400 mg/kg) on scopolamine-invoked neurotoxicity in brain were studied. During the experimental period, behaviour analyses of rats were observed 30 min post-drug administration. The role of antioxidants of HAPT in scavenging cellular oxygen/peroxyl radicals were studied. Acetylcholinesterase and butyrylcholinesterase inhibitions, and mode of inhibition kinetics of HAPT were studied. Pathogenic cellular oxidative (MDA, GSH, SOD, and CAT), DNA damage (8-oxodG), neurochemical (acetyl- and, butyryl-cholinesterase), ß-secretase (BACE-1 and 2), MAPτ, and neuroinflammation (IL-6, TNF-α) biomarkers in extension to the histopathological observation of brain cortex were studied. GC-MS/MS analysis was carried out to investigate the presence of bioactive constituents in HAPT. RESULTS: HAPT, a rich source of phenol and flavonoid type antioxidants were responsible in quenching oxygen/peroxyl radicals and protected the cellular membrane, and lipoproteins against ROS in DPPH, ORAC, and CAPe tests. HAPT inhibited acetylcholinesterase and butyrylcholinesterase activities, and showed competitive-inhibition (reversible) towards cholinesterase activities. HAPT-400 significantly improved the learning and memory-impairment by restoring oxidative MDA, GSH, SOD, CAT, and DNA damage (8-oxodG) markers of serum, and cortex. It also improved acetyl- and, butyryl-cholinesterase, ß-secretase, and MAPτ level in brain by restoring proinflammatory cytokines IL-6, and TNF-α indicators in neurotoxic rats. GC-MS/MS reported therapeutic significance active compounds were molecular-docked towards target proteins, found that proscillaridin showed the highest affinity towards AChE, BuChE, BACE1, and BACE2 with binding energy of ΔGb -9.1, ΔGb -10.2, ΔGb -11.4 and ΔGb -11.5 Kcal/mol, respectively. Cymarin and morphine-3-glucuronide showed the second highest binding affinity towards AChE (ΔGb -8.8) and BuChE (ΔGb -10.0), respectively. In BACE-1, betulin showed the second highest binding affinity ΔGb -10.7 Kcal/mol and in BACE-2, morphine-3-glucuronide showed the second highest binding affinity ΔGb -9.8 Kcal/mol. CONCLUSIONS: Synergistic impact of proscillaridin, Cymarin, morphine-3-glucuronide, betulin like compounds in HAPT improved memory impairment, healing of tissue architecture of cortex with the restoration of neurochemical, neuroinflammation, and oxidative indicators in neurotoxic rats.


Assuntos
Piper , Proscilaridina , Ratos , Animais , Escopolamina/farmacologia , Secretases da Proteína Precursora do Amiloide , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Ratos Wistar , Piper/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Cimarina , Interleucina-6 , Doenças Neuroinflamatórias , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ácido Aspártico Endopeptidases/metabolismo , Superóxido Dismutase , Cognição , Oxigênio , Inibidores da Colinesterase/farmacologia
3.
J Ethnopharmacol ; 318(Pt A): 116881, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37460029

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Petiveria alliacea L., commonly known as macura and gully root, is an important medicinal plant used in the Caribbean and Central America to treat ailments associated to the central nervous system, including poor memory. AIM OF THE STUDY: To assess the effects of the P. alliacea leaves methanol fraction (PMF) on a scopolamine-induced learning and memory impairment mouse model related to acetylcholinesterase activity and oxidative stress. MATERIAL AND METHODS: After PMF administration at doses of 500 or 900 mg/kg, cognitive ability was evaluated using the Morris water maze (MWM), Y-maze (YM) and novel object recognition (NOR) tests. The mouse brain tissue was further assessed for acetylcholinesterase activity and antioxidant activity. Levels of oxidative stress were also evaluated by measuring malondialdehyde (MDA) and glutathione activity. Acute toxicity was also evaluated. RESULTS: PMF led to memory improvement in the behavioral tests in mice with scopolamine-induced cognitive impairment. Moreover, PMF inhibited acetylcholinesterase activity and showed antioxidant potential that in turn attenuated cholinergic degradation. Additionally, PMF increased glutathione levels and glutathione reductase activity and reduced MDA levels in the brain. Moreover, no acute toxicity was detected with the use of PMF. CONCLUSION: In a mouse model of scopolamine-induced cognitive deficit, PMF exhibited protective effects, decreasing oxidative damage and regulating cholinergic function in the brain bearing significant memory enhancing potency. These data suggest that PMF is a promising candidate for developing therapies for neurodegenerative disorders.


Assuntos
Fármacos Neuroprotetores , Phytolaccaceae , Camundongos , Animais , Escopolamina/toxicidade , Acetilcolinesterase/metabolismo , Fármacos Neuroprotetores/efeitos adversos , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Estresse Oxidativo , Glutationa/metabolismo , Colinérgicos/farmacologia , Extratos Vegetais/efeitos adversos
4.
J Ethnopharmacol ; 318(Pt B): 116995, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37541399

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Olax subscorpioidea oliv. is a shrub plant of the Olacaceae family with reported usage in ethnomedicine as a nootropic agent for the management of Alzheimer's-like dementia. AIM: The aim of this study is to investigate the nootropic potential of methanol extract of Olax subscorpioidea (MEOS) in scopolamine-induced Alzheimer's-like dementia. MATERIALS AND METHODS: Thirty male mice, assigned into six groups (n = 8), were used for this study. Group, I received distilled water, group II received scopolamine (1 mg/kg, i.p.), groups iii-v received 25, 50, and 100 mg/kg, p.o. of MEOS and scopolamine (1 mg/kg/i.p.), and group vi received donepezil 5 mg/kg, p.o.and scopolamine (1 mg/kg, i.p.). The animals were pre-treated with MEOS and Donepezil for 14 days, and scopolamine from the 8th to 14th day. Followed by cognitive, oxidative stress, neuroinflammation, and histology assessments. RESULTS: 100 mg/kg MEOS significantly reduced transfer latency and increased discrimination index in the elevated plus maze and novel object recognition test cognitive assessments. 100 mg/kg MEOS, significantly reduced oxidative stress, protect endogenous antioxidants, suppressed neuroinflammation, and acetylcholinesterase (ACHE) activity. The histomorphometry study of the hippocampus revealed that MEOS prevented extensive pyknosis, karyolysis, chromatolysis, and loss of hippocampal neurons that accompanied scopolamine treatment. CONCLUSION: MEOS protected against Alzheimer's-like dementia via the suppression of neuroinflammation and oxidative stress associated with scopolamine-induced amnesic behavior.


Assuntos
Doença de Alzheimer , Nootrópicos , Olacaceae , Camundongos , Animais , Escopolamina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Donepezila/farmacologia , Doenças Neuroinflamatórias , Extratos Vegetais/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Colinérgicos/farmacologia , Estresse Oxidativo , Nootrópicos/farmacologia , Hipocampo/metabolismo , Aprendizagem em Labirinto
5.
Bioorg Chem ; 142: 106916, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37913584

RESUMO

Development of Multitarget-Directed Ligands (MTDLs) is a promising approach to combat the complex etiologies of Alzheimer's disease (AD). Herein we report the design, synthesis, and characterization of a new series of 1,4-bisbenzylpiperazine-2-carboxylic acid derivatives 3-5(a-g), 7a-f, 8a-s, and their piperazine-2-yl-1,3,4-oxadiazole analogs 6a-g. In vitro inhibitory effect against Electrophorus electricus acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from Equine serum was evaluated using modified Ellman's method, considering donepezil and tacrine as reference drugs. Lineweaver-Burk plot analysis of the results proved competitive inhibition of AChE and BChE with Ki values, in low micromolar range. The free carboxylic acid series 4a-g showed enhanced selectivity for AChE. Hence, 4c, 1,4-bis (4-chlorobenzyl)-piperazinyl-2-carboxylic acid), was the most active member of this series (Ki (AChE) = 10.18 ± 1.00 µM) with clear selectivity for AChE (SI âˆ¼ 17.90). However, the hydroxamic acids 7a-f and carboxamides 8a-s congeners were more potent and selective inhibitors of BChE (SI âˆ¼ 5.38 - 21862.5). Extraordinarily, 1,4-bis (2-chlorobenzyl)-piperazinyl-2-hydroxamic acid 7b showed promising inhibitory activity against BChE enzyme (Ki = 1.6 ± 0.08 nM, SI = 21862.5), that was significantly superior to that elicited by donepezil (Ki = 12.5 ± 2.6 µM) and tacrine (Ki = 17.3 ± 2.3 nM). Cytotoxicity assessment of 4c and 7b, on human neuroblastoma (SH-SY5Y) cell lines, revealed lower toxicity than staurosporine and was nearly comparable to that of donepezil. Molecular docking and molecular dynamics simulation afforded unblemished insights into the structure-activity relationships for AChE and BChE inhibition. The results showed stable binding with fair H-bonding, hydrophobic and/or ionic interactions to the catalytic and peripheral anionic sites of the enzymes. In silico predicted ADME and physicochemical properties of conjugates showed good CNS bioavailability and safety parameters. In this regard, compound (7b) might be considered as a promising inhibitor of BChE with an innovative donepezil-based anti-Alzheimer activity. Further assessments of the most potent AChE and BChE inhibitors as potential MTDLs anti-Alzheimer's agents are under investigation with our research group and will be published later.


Assuntos
Doença de Alzheimer , Neuroblastoma , Animais , Cavalos , Humanos , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Donepezila/farmacologia , Acetilcolinesterase/metabolismo , Tacrina/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/farmacologia , Ácidos Carboxílicos , Relação Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico , Simulação de Dinâmica Molecular , Estrutura Molecular
6.
Sci Total Environ ; 908: 168043, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37898196

RESUMO

Pharmaceutical transformation products (TPs) generated during wastewater treatment have become an environmental concern. However, there is limited understanding regarding the TPs produced from pharmaceuticals during wastewater treatment. In this study, chloroquine (CQ), which was extensively used for treating coronavirus disease-19 (COVID-19) infections during the pandemic, was selected for research. We identified and fractionated the main TP produced from CQ during chlorine disinfection and investigated the neurotoxic effects of CQ and its main TP on zebrafish (Danio rerio) embryos. Halogenated TP353 was observed as one of the main TPs produced from CQ during chlorine disinfection. Zebrafish embryos test revealed that TP353 caused higher neurotoxicity in zebrafish larvae, as compared to the CQ, and that was accompanied by significantly decreased expression levels of the genes related to central nervous system development (e.g., gfap, syn2a, and elavl3), inhibited activity of acetylcholinesterase (AChE), reduced GFP fluorescence intensity of motor neuron axons in transgenic larvae (hb9-GFP), and reduced total swimming distance and swimming velocity of larvae during light-dark transition stimulation. The results of this study can potentially be utilized as a theoretical reference for future evaluations of environmental risks associated with CQ and its related TPs. This work presents a methodology for assessing the environmental hazards linked to the discharge of pharmaceutical TPs after wastewater treatment.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Peixe-Zebra/fisiologia , Acetilcolinesterase/metabolismo , Cloro/metabolismo , Halogenação , Cloroquina/toxicidade , Preparações Farmacêuticas/metabolismo , Poluentes Químicos da Água/metabolismo , Larva
7.
Food Chem ; 437(Pt 1): 137905, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37922803

RESUMO

The walnut meal is rich in nutrients such as protein from the kernel and polyphenolic compounds from the seed coat. However, the influences of seed coat polyphenols on walnut protein (WP) hydrolysis remained unclear. In this study, our findings indicated that polyphenols induced alterations in the secondary structure and amino acid composition of WP. These changes resulted in both a hindrance of hydrolysis and an enhancement of acetylcholinesterase (AChE) inhibition. Furthermore, four peptides of 119 identified peptides (LR, SF, FQ, and FR) were synthesized based on higher predicted bioactivity and Vinascores in silico. Among them, FQ showed interaction with amino acid residues in AChE through the formation of four π-π stacking bonds and two hydrogen bonds, resulting in the highest AChE inhibitory capacity. The combination index showed that chlorogenic acid derived from the seed coat and FQ at the molar ratio of 1:4 exhibited synergistic effects of AChE inhibition.


Assuntos
Juglans , Juglans/química , Polifenóis/farmacologia , Polifenóis/análise , Acetilcolinesterase/metabolismo , Hidrólise , Hidrolisados de Proteína/química , Sementes/química , Peptídeos/química , Aminoácidos/análise
8.
Sci Total Environ ; 908: 168403, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37939945

RESUMO

Benzophenone-3 (BP-3) is the most widely used ultraviolet filter (UV filter) in industries to avoid UV radiation damage. BP-3 is added to most sunscreens to protect the skin, hair, and lips from sun rays. It results in continuous discharge into aquatic environments, leading to aquatic biota and human's continuous exposure. Consequences of BP-3 exposure on the physiology and behavior of aquatic animals, mainly zebrafish, have been investigated, including their neurotoxic effects. However, little is known about its consequences in long-term developmental endpoints. This study aimed to investigate the long-term effects of embryonic BP-3 exposure on biomarkers of neurotoxicity in zebrafish. For this, we exposed embryos to 5, 10, and 20 µg∙L-1 BP-3 concentration and let fish grow to adulthood (5mpf). We evaluated anxiety-like behavior, social preference, aggressiveness, and enzymatic activity of the antioxidant defenses system and neurotoxic biomarkers (Glutathione S-transferase -GST, catalase -CAT, and acetylcholinesterase -AChE) in adult zebrafish. Enzymatic activities were also investigated in larvae immediately after BP-3 exposure. Animals early exposed to BP-3 presented anxiety-like behaviors and decreased social preference, but aggressiveness was not altered. In general, exposure to BP-3 leads to altered enzymatic activity, which persists into adulthood. GST activity increased in embryos and adults, while CAT activity decreased in both life stages. AChE activity enhanced only at the larval stage (96 hpf). The long-term behavioral and biochemical effects of BP-3 highlight the need for abolishing or restricting the compound from personal care products, which are continually disposed into the environment and threaten the biota and human health.


Assuntos
Estresse Oxidativo , Poluentes Químicos da Água , Animais , Humanos , Peixe-Zebra , Acetilcolinesterase/metabolismo , Biomarcadores/metabolismo , Poluentes Químicos da Água/metabolismo , Embrião não Mamífero , Larva
9.
J Hazard Mater ; 462: 132644, 2024 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-37820532

RESUMO

Dibutyl phthalate (DBP) is one of the most commonly utilized plasticizers and a frequently detected phthalic acid ester (PAE) compound in soil samples. However, the toxicological effects of DBP on soil-dwelling organisms remain poorly understood. This study employed a multi-biomarker approach to investigate the impact of DBP exposure on Folsomia candida's survival, reproduction, enzyme activity levels, and transcriptional profiles. Analyses of antioxidant biomarkers, including catalase (CAT) and glutathione S-transferase (GST), as well as detoxifying enzymes such as acetylcholinesterase (AChE), Cytochrome P450 (CYP450), and lipid peroxidation (LPO), revealed significant increases in CAT activity, GST levels, and CYP450 expression following treatment with various doses of DBP for 2, 4, 7, or 14 days. Additionally, LPO induction was observed along with significant AChE inhibition. In total, 3175 differentially expressed genes (DEGs) were identified following DBP treatment that were enriched in six Gene Ontology (GO) terms and 144 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including 85 upregulated and 59 downregulated primarily associated with lipid metabolism, signal transduction, DNA repair, and cell growth and death. Overall these results provide foundational insights for further research into the molecular mechanisms underlying responses of soil invertebrates to DBP exposure.


Assuntos
Artrópodes , Dibutilftalato , Animais , Dibutilftalato/toxicidade , Transcriptoma , Solo , Acetilcolinesterase/metabolismo , Antioxidantes/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Invertebrados/metabolismo , Artrópodes/genética , Artrópodes/metabolismo
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 305: 123452, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37769468

RESUMO

The search for acetylcholinesterase (AChE) inhibitors produced by natural sources is of great significance for the prevention and therapy of Alzheimer's disease and has been widely concerned. In this study, fisetin, a flavonoid compound of plant origin, displayed a mixed inhibition mode on AChE (IC50 = 8.88 ± 0.14 µM). Fluorescence spectra analysis revealed that fisetin statically quenched AChE fluorescence, and the ground state complex was formed by hydrogen bonds and hydrophobic interactions. Circular dichroism assays showed that fisetin induced AChE structure loosened with a decrease in α-helix structure (from 20.6 % to 19.5 %). Computer simulation exhibited that fisetin bound to both the peripheral anionic site (PAS) and the catalytic active site (CAS) and increased the stability of the AChE. Interestingly, the combination of fisetin and galantamine enhanced the binding affinity between AChE and galantamine and induced AChE structure further loosened, while the inhibition mode was still the mixed type. The heatmap analysis indicated that galantamine (0.2 µM) combined with fisetin (2.25 µM) had a significant synergy on AChE inhibition, probably because fisetin binding at the PAS-AChE induced conformation changes of the gorge and CAS, which enhanced galantamine binding affinity with CAS, and a further loose structure of AChE was induced by the mixture, so finally the interaction between the substrate and AChE was strongly affected. This work may offer a theoretical reference for the functional research of fisetin as a potential AChE inhibitor and an enhanced supplement for galantamine.


Assuntos
Doença de Alzheimer , Galantamina , Humanos , Galantamina/química , Galantamina/farmacologia , Acetilcolinesterase/metabolismo , Simulação por Computador , Inibidores da Colinesterase/química , Doença de Alzheimer/metabolismo , Domínio Catalítico , Simulação de Acoplamento Molecular
11.
J Ethnopharmacol ; 319(Pt 1): 117106, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37652198

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a progressive developmental neurodegenerative disease that primarily develops in old age. Memory impairment is an important manifestation of AD. It has been demonstrated that inflammation and oxidative stress are important mediators in the development and progression of AD. Codonopsis Radix (CR) has a long history of consumption, exhibiting lots of beneficial health effects, including anti-ageing, antioxidant, and anti-inflammatory properties. However, studies on the effects of CR on scopolamine-induced amnesia have rarely been reported. AIM OF THE STUDY: The aim of this study was to investigate the ameliorative effect of macromolecular portion (polysaccharides, POL) and small molecule portion (fine extract rich in phenylpropanoids-polyacetylenes, EPP) from CR on improving scopolamine-induced memory impairment and to elucidate the potential mechanism of action. MATERIALS AND METHODS: C57BL/6 mice were pretreated with EPP (0.2, 0.4, and 0.6 g/kg), POL (0.3, 0.6, and 0.9 g/kg), and donepezil (5 mg/kg) by gavage for 7 days, followed by intraperitoneal injection of scopolamine (1 mg/kg) to induce memory impairment. The 16S rRNA gene sequencing, histopathological, western blotting, and biochemical analysis (various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation) were performed to further elucidate the mechanism of action. Moreover, the acetylcholinesterase (AChE) inhibitory activities of POL, EPP, and its main compounds tangshenoside I, lobetyol, lobetyolin, and lobetyolinin were evaluated. RESULTS: Experiments have confirmed that both POL and EPP from CR could improve scopolamine-induced spatial learning memory deficits. Both of them could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities. They also could enhance antioxidant defense via increasing the activities of superoxide dismutase and glutathione peroxidase, and anti-inflammatory function through suppressing inflammatory factors (nitric oxide, TNF-α, and IL-6) and regulating gut flora. Besides, in vitro experiments demonstrated that four monomeric compounds and EPP, except POL, exhibited inhibition of AChE activity. CONCLUSION: EPP and POL from CR exert a beneficial effect on learning and memory processes in mice with scopolamine-induced memory impairment. CR may be a promising medicine for preventing and improving learning memory.


Assuntos
Doença de Alzheimer , Codonopsis , Doenças Neurodegenerativas , Camundongos , Animais , Escopolamina/toxicidade , Antioxidantes/farmacologia , Polímero Poliacetilênico/metabolismo , Polímero Poliacetilênico/farmacologia , Acetilcolinesterase/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , RNA Ribossômico 16S/metabolismo , Camundongos Endogâmicos C57BL , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Estresse Oxidativo , Doença de Alzheimer/tratamento farmacológico , Colinérgicos/farmacologia , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Anti-Inflamatórios/farmacologia , Aprendizagem em Labirinto
12.
J Ethnopharmacol ; 319(Pt 1): 117151, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37689325

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Laurus nobilis L. (Lauraceae family) has been widely used in traditional Tunisian medicine for the treatment of different health problems such as rheumatism and some neurological disorders. AIM: In this study, the essential oil obtained from Laurus nobilis L. species from Tunisia (LEO) was studied for its chemical composition and anti-amnesic activities on memory impairment caused by scopolamine injection in mice. The major compounds of LEO oil, 1,8-cineole and, α-terpinyl acetate were docked with AChE (Acetylcholinesterase), using Autodock Vina and Discovery Studio visualizer software. MATERIALS AND METHODS: The Morris water maze (MWM) tests and the Y maze were used to assess the anti-amnesic effects of LEO in mice with scopolamine-induced memory impairments. In brain tissues, the levels of biomarkers, enzyme activity, and protein expression related to the cholinergic system were measured. RESULTS: Chronic administration of scopolamine led to a significant decline in cognitive performance in both the Morris Water Maze (MWM) and Y maze tests, accompanied by pronounced oxidative damage and a significant increase in acetylcholinesterase activity compared to the other groups. However, compared to the scopolamine group, treatment with LEO (100 mg/kg) significantly enhanced cognitive function and ameliorated the oxidative damage (p < 0.05 versus scopolamine) CONCLUSION: This study demonstrates the beneficial effect of LEO on scopolamine-induced dementia in mice, potentially achieved through the modulation of cholinergic activity and antioxidant properties. The docking analysis of the major compounds, 1,8-cineole and α-terpinyl acetate, further substantiates their potential as memory enhancers.


Assuntos
Laurus , Fármacos Neuroprotetores , Óleos Voláteis , Camundongos , Animais , Escopolamina/toxicidade , Acetilcolinesterase/metabolismo , Laurus/metabolismo , Óleos Voláteis/efeitos adversos , Eucaliptol/farmacologia , Eucaliptol/uso terapêutico , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Estresse Oxidativo , Aprendizagem em Labirinto , Encéfalo , Colinérgicos/farmacologia , Fármacos Neuroprotetores/efeitos adversos
13.
Am J Alzheimers Dis Other Demen ; 38: 15333175231211082, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37977137

RESUMO

Previous studies have demonstrated that exercise improves cognitive function in Alzheimer's disease mice but the exact mechanism needs further studies. This research aimed to study the effects of aerobic treadmill exercise on epidermal growth factor (EGF) levels and learning and memory in d-galactose-induced aging in a mouse model. Forty male Kunming mice were analyzed in this study and randomly divided into 4 groups: control (C group), aerobic exercise (AE group), d-galactose (D-gal group), and d-galactose + aerobic exercise (D-gal + AE group). The C and AE groups received a daily mid-scapular subcutaneous injection of .9% saline for 40 days. Mice in the D-gal and D-gal + AE groups were subcutaneously injected with d-galactose (1.25 mg/kg) once daily for 40 days. The mice in the AE group and D-gal + AE group completed 40 days of aerobic treadmill exercise. Learning and memory were evaluated by step-down tests. Specifically, 24 h after the behavioral test, blood was collected and brain tissue was extracted, and superoxide dismutase (SOD) and acetylcholinesterase activities were detected. The neurons in the CA1 and CA3 regions of the hippocampus were counted by Nissl staining. The number of EGF-positive cells was observed by immunohistochemical methods. In the learning test, the reaction time in the D-gal group increased significantly (P < .05), while the error numbers in the D-gal group tended to decrease compared with AE, D-gal + AE, and C groups. In the memory test, the latency of mice in the D-gal group was lower, while the error in this group was higher than in the other groups (P < .05). The activities of SOD and acetylcholinesterase were lower in the D-gal group than in the other groups (P < .05). The number of EGF-positive cells and neurons in the hippocampal CA1 and CA3 regions in the D-gal + AE group was higher compared to those in the D-gal group (P < .05), and lower in groups with mice that were not injected with d-galactose. Aerobic treadmill exercise inhibited SOD activity, increased EGF-positive cells, and decreased neuronal death and apoptosis, thereby improving learning and memory in the mouse model of d-galactose-induced aging.


Assuntos
Acetilcolinesterase , Galactose , Camundongos , Masculino , Animais , Galactose/metabolismo , Galactose/farmacologia , Acetilcolinesterase/metabolismo , Acetilcolinesterase/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Envelhecimento , Hipocampo , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Estresse Oxidativo
14.
J Evid Based Integr Med ; 28: 2515690X231211661, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37960857

RESUMO

Amaranthus dubius is a vegetable consumed for its nutritional content in Kenya. In herbal medicine, A. dubius is utilized to relief fever, anemia and hemorrhage. Additionally, it is utilized to manage cognitive dysfunction and is considered to augment brain function, but there is no empirical evidence to support this claim. The contemporary study investigated cognitive enhancing potential of A. dubius in mice model of Alzheimer's disease (AD)-like dementia induced with ketamine. Cognitively damaged mice were treated with aqueous extract of A. dubius leaf upon which passive avoidance task (PAT) was used to assess the cognitive performance. At the end of passive avoidance test, brains of the mice were dissected to evaluate the possibility of the extract to inhibit hallmarks that propagate AD namely oxidative stress and acetylcholinesterase activity. Additionally, characterization of secondary metabolites was done using liquid chromatograph- mass spectrometry analysis. During PAT test, extract-treated mice showed significantly increased step-through latencies than AD mice, depicting ability of A. dubius to reverse ketamine-induced cognitive decline. Further, the extract remarkably lowered malondialdehyde levels to normal levels and effectively inhibited acetylcholinesterase enzyme. The study showed that A. dubius extract is endowed with phytoconstituents that possess anti-oxidant and anticholinesterase activities. Thus, this study confirmed promising therapeutic effects of 200, 300 and 400 mg/kg bw of A. dubius extract with potential to alleviate cognitive disarray observed in AD.


Assuntos
Doença de Alzheimer , Ketamina , Camundongos , Animais , Acetilcolinesterase/metabolismo , Acetilcolinesterase/farmacologia , Ketamina/efeitos adversos , Cognição , Extratos Vegetais/uso terapêutico
15.
Mar Drugs ; 21(11)2023 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-37999391

RESUMO

The coral-derived fungus Aspergillus austwickii SCSIO41227 from Beibu Gulf yielded four previously uncharacterized compounds, namely asperpentenones B-E (1-4), along with twelve known compounds (5-16). Their structures were elucidated using HRESIMS and NMR (1H and 13C NMR, HSQC, HMBC), among which the stereo-structure of compounds 1-3 was determined by calculated ECD. Furthermore, compounds 1-16 were evaluated in terms of their enzyme (acetylcholinesterase (AChE), pancreatic lipase (PL), and neuraminidase (NA)) inhibitory activities. These bioassay results revealed that compounds 2 and 14 exerted noticeable NA inhibitory effects, with IC50 values of 31.28 and 73.64 µM, respectively. In addition, compound 3 exhibited a weak inhibitory effect against PL. Furthermore, these compounds showed the potential of inhibiting enzymes in silico docking analysis to demonstrate the interactions between compounds and proteins.


Assuntos
Antozoários , Neuraminidase , Animais , Lipase/metabolismo , Acetilcolinesterase/metabolismo , Aspergillus/química , Antozoários/metabolismo , Estrutura Molecular
16.
Int J Mol Sci ; 24(22)2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-38003406

RESUMO

Congenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been characterized as being biochemical and functional. They are responsible for the structure of the protein in the triple helix and the association of COLQ with acetylcholinesterase. To deepen the analysis of the distal C-terminal peptide properties and understand the CMSs associated to pathogenic variants in this domain, we have analyzed the case of a 32 year old male patient bearing a homozygote splice site variant c.1281 C > T that changes the sequence of the last 28 aa in COLQ. Using COS cell and mouse muscle cell expression, we show that the COLQ variant does not impair the formation of the collagen triple helix in these cells, nor its association with acetylcholinesterase, and that the hetero-oligomers are secreted. However, the interaction of COLQ variant with LRP4, a signaling hub at the neuromuscular junction, is decreased by 44% as demonstrated by in vitro biochemical methods. In addition, an increase in all acetylcholine receptor subunit mRNA levels is observed in muscle cells derived from the patient iPSC. All these approaches point to pathophysiological mechanisms essentially characterized by a decrease in signaling and the presence of immature acetylcholine receptors.


Assuntos
Síndromes Miastênicas Congênitas , Masculino , Humanos , Animais , Camundongos , Adulto , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Junção Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Colágeno/metabolismo , Mutação
17.
Int J Mol Sci ; 24(22)2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38003650

RESUMO

This study investigated the neuroprotective effects of Dendropanax morbifera leaves and stems (DMLS) water extract on scopolamine (SCO)-induced memory impairment in mice. First, we conducted experiments to determine the protective effect of DMLS on neuronal cells. Treatment with DMLS showed a significant protective effect against neurotoxicity induced by Aß(25-35) or H2O2. After confirming the neuroprotective effects of DMLS, we conducted animal studies. We administered DMLS orally at concentrations of 125, 250, and 375 mg/kg for 3 weeks. In the Y-maze test, SCO decreased spontaneous alternation, but treatment with DMLS or donepezil increased spontaneous alternation. In the Morris water-maze test, the SCO-treated group showed increased platform reach time and decreased swim time on the target platform. The passive avoidance task found that DMLS ingestion increased the recognition index in short-term memory. Furthermore, memory impairment induced by SCO reduced the ability to recognize novel objects. In the Novel Object Recognition test, recognition improved with DMLS or donepezil treatment. In the mouse brain, except for the cerebellum, acetylcholinesterase activity increased in the SCO group and decreased in the DMLS and donepezil groups. We measured catalase and malondialdehyde, which are indicators of antioxidant effectiveness, and found that oxidative stress increased with SCO but was mitigated by DMLS or donepezil treatment. Thus, our findings suggest that ingestion of DMLS restored memory impairment by protecting neuronal cells from Aß(25-35) or H2O2-induced neurotoxicity, and by reducing oxidative stress.


Assuntos
Fármacos Neuroprotetores , Escopolamina , Camundongos , Animais , Escopolamina/efeitos adversos , Fármacos Neuroprotetores/efeitos adversos , Peróxido de Hidrogênio/farmacologia , Água/farmacologia , Acetilcolinesterase/metabolismo , Donepezila/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo , Aprendizagem em Labirinto , Extratos Vegetais/efeitos adversos
18.
J Enzyme Inhib Med Chem ; 38(1): 2281264, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37985494

RESUMO

A library of N-benzylpyridinium-based compounds, 7a-j and 8a-j, was designed and synthesised as potential acetylcholinesterase) AChE (inhibitors. An in vitro assay for the synthesised compounds showed that most compounds had significant AChE inhibitory activities at the nanomolar and submicromolar levels. The benzyl (8a) and fluoro (8b) derivatives were the most active, with IC50 values ≤56 nM. Compound 7f, which had a benzyl moiety, showed the highest potency among all the target compounds, with an IC50 value of 7.5 ± 0.19 nM against AChE, which was higher than that of the activities of tacrine (IC50 = 30 ± 0.2 nM) and donepezil (IC50 = 14 ± 0.12 nM). Compounds with vanillin moieties exhibited antioxidant activity. Among the tested compounds, four derivatives (7f, 7 g, 8f, and 8 g) exhibited superior AChE inhibitory activity, with Ki values of 6-16 nM, which were potent in the same range as the approved drug, donepezil. These compounds showed moderate antioxidant activities, as indicated by the results of the ABTS assay.


Assuntos
Doença de Alzheimer , Curcumina , Humanos , Donepezila , Inibidores da Colinesterase/farmacologia , Antioxidantes/farmacologia , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Dor , Simulação de Acoplamento Molecular
19.
J Agric Food Chem ; 71(47): 18359-18374, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-37965968

RESUMO

Plants employ abundant toxic secondary metabolites to withstand insect attack, while pollinators can tolerate some natural defensive compounds. Coumarins, as promising green alternatives to chemical insecticides, possess wide application prospects in the crop protection field. Herein, the bioactivities of 30 natural coumarin derivatives against Aphis gossypii were assessed and revealed that 6-methylcoumarin exhibited potent aphicidal activity against aphids but displayed no toxicity to honeybees. Additionally, using biochemical, bioinformatic, and molecular assays, we confirmed that the action mode of 6-methylcoumarin against aphids was by inhibiting acetylcholinesterase (AChE). Meanwhile, functional assays revealed that the difference in action site, which located in Lys585 in aphid AChE (equivalent to Val548 in honeybee AChE), was the principal reason for 6-methylcoumarin being toxic to aphids but safe to pollinators. This action site was further validated by mutagenesis data, which uncovered how 6-methylcoumarin was unique selective to the aphid over honeybee or mammalian AChE. Furthermore, a 2D-QSAR model was established, revealing that the central structural feature was H3m, which offers guidance for the future design of more potent coumarin compounds. This work provides a sustainable strategy to take advantage of coumarin analogues for pest management while protecting nontarget pollinators.


Assuntos
Afídeos , Inseticidas , Animais , Inseticidas/farmacologia , Afídeos/metabolismo , Acetilcolinesterase/metabolismo , Relação Quantitativa Estrutura-Atividade , Insetos/metabolismo , Mamíferos/metabolismo
20.
PLoS One ; 18(11): e0286349, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37910530

RESUMO

OBJECTIVE: Berberis lycium is an indigenous plant of Pakistan that is known for its medicinal properties. In the current study, we investigated the anti-Alzheimer's effect of berberine isolated from Berberis lycium. METHODS: Root extract of B. lycium was subjected to acetylcholinesterase inhibition assay and column chromatography for bioassays guided isolation of a compound. The neuroprotective and memory improving effects of isolated compound were evaluated by aluminium chloride induced Alzheimer's disease rat model, elevated plus maze (EPM) and Morris water maze (MWM) tests., Levels of dopamine and serotonin in rats brains were determined using HPLC. Moreover, western blot and docking were performed to determine interaction between berberine and ß-secretase. RESULTS: During fractionation, ethyl acetate and methanol (3:7) fraction was collected from solvent mixture of ethyl acetate and methanol. This fraction showed the highest anti-acetylcholinesterase activity and was alkaloid positive. The results of TLC and HPLC analysis indicated the presence of the isolated compound as berberine. Additionally, the confirmation of isolated compound as berberine was carried out using FTIR and NMR analysis. In vivo EPM and MWM tests showed improved memory patterns after berberine treatment in Alzheimer's disease model. The levels of dopamine, serotonin and activity of antioxidant enzymes were significantly (p<0.05) enhanced in brain tissue homogenates of berberine treated group. This was supported by decreased expression of ß-secretase in berberine treated rat brain homogenates and good binding affinity of berberine with ß-secretase in docking studies. Binding energies for interaction of ß-secretase with berberine and drug Rivastigmine is -7.0 kcal/mol and -5.8 kcal/mol respectively representing the strong interactions. The results of docked complex of secretase with berberine and Rivastigmine was carried out using Gromacs which showed significant stability of complex in terms of RMSD and radius of gyration. Overall, the study presents berberine as a potential drug against Alzheimer's disease by providing evidence of its effects in improving memory, neurotransmitter levels and reducing ß-secretase expression in the Alzheimer's disease model.


Assuntos
Doença de Alzheimer , Berberina , Berberis , Lycium , Fármacos Neuroprotetores , Ratos , Animais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Berberina/farmacologia , Berberina/uso terapêutico , Berberis/química , Berberis/metabolismo , Cloreto de Alumínio , Lycium/metabolismo , Simulação de Acoplamento Molecular , Rivastigmina/farmacologia , Rivastigmina/uso terapêutico , Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Dopamina , Metanol , Serotonina/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
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