Brain Acetylcholinesterase Activity Research Articles

Response of oxidative stress and neurotoxicity biomarkers in rainbow trout (Oncorhynchus mykiss) after exposure to six-metal mixtures

ABSTRACT The activity of liver catalase and brain acetylcholinesterase was assessed in rainbow trout (Oncorhynchus mykiss) after 7- and 14-day exposure to a six-metal mixture at the maximum permissible concentrations accepted for inland waters in the EU (2013/39/EU; 2008/105/EC) (Zn − 0.1, Ni − 0.034, Cu − 0.01, Cr − 0.01, Cd − 0.0015 and Pb − 0.014 mg L−1) and to the same six-metal mixtures with tenfold reduced concentration of Cu and Cr ions. A statistically significant increase of up to 26% of catalase and 52% of acetylcholinesterase activity was observed in rainbow trout after 7 days of exposure to the six-metal mixture at the maximum permissible concentrations in comparison to a control group. After 14-day treatment, neither CAT nor AChE showed significant response to all tested metal mixtures. The six-metal mixture with the tenfold reduced concentration of Cr increased brain AChE activity in O. mykiss after 7 days of exposure (35%). Enhancement of catalase activity caused by the mixture of the six metals at the maximum permissible concentrations and the increased acetylcholinesterase activity in response to the same metal mixture and mixture with tenfold reduced Cr concentration after 7 days of exposure indicates the induction of oxidative stress and disturbance of cholinergic system homeostasis respectively.

Hexaflumuron insecticide exposure induces behavior alterations, hemato-biochemical disorders, antioxidant-immune dysfunction, and histopathological alterations in Nile tilapia (Oreochromis niloticus).

Hexaflumuron (HEX) insecticide is widely used in agriculture practices to fight crop insects. The toxicological effect of HEX on Nile tilapia (Oreochromis niloticus) was investigated in this study. Two hundred and forty fish (35.50 ± 1.45 g) were divided into six groups in four replicates (40 fish/group; 10 fish/replicate) and were exposed to six distinct HEX concentrations (0, 2, 4, 6, 8, and 10 mg L-1) for 96-h. The 96-h lethal concentration 50 (96-h LC50) of HEX was calculated to be 7.19 mg L-1. The fish exhibited reduced surface and middle swimming, aggressiveness, and tail-spreading behaviors with increasing bottom swimming and resting patterns after HEX exposure. HEX exposure resulted in body bleeding and fin rot. The erythrogram (red blood cell count, hemoglobin, and packed cell volume %) was significantly reduced with increased mean corpuscular volume by HEX exposure. HEX exposure decreased the white blood cells (WBCs) and differential WBC counts. Acute HEX exposure raised 8-hydroxy-2-deoxyguanosine level while lowering brain acetylcholine esterase activity. HEX exposure caused hepato-renal dysfunction and increased stress-related parameters (glucose and cortisol). Exposure to HEX reduced the immune responses (lysozyme, nitric oxide, immunoglobulin M, and complement 3). A substantial decrease in the antioxidant variables (reduced glutathione content and catalase) with increasing the malondialdehyde was noted by HEX exposure. Moreover, histopathological changes resulted from HEX exposure in the gills, liver, kidney, and spleen. These results indicate that HEX exposure induced behavioral changes, hepato-renal dysfunction, and immune-antioxidant disruption, indicating a possible physiological disruption in O. niloticus.

Whey protein hydrolysate intervention ameliorates memory deficits in APP/PS1 mice: Unveiling gut microbe–short‐chain fatty acid–brain axis

AbstractThe intricate causes of Alzheimer's disease (AD) hinder effective, lasting treatment. Although the dietary modulation of the brain–gut axis was explored for AD therapy, the exact mechanism remains unclear. This study suggested that 140 days of the whey protein hydrolysate (WPH) intake could attenuate the AD pathologic symptoms in APP/PS1 transgenic mice via a bidirectional action of the gut microbe–SCFA (short‐chain fatty acid)–brain axis. Behavioral tests demonstrated that high‐dose WPH (WPH‐H, 100 mg/kg body weight [bw]) improved passive and recognition memory in mice. Furthermore, WPH‐H significantly reduced amyloid beta 1–42 (Aβ1–42) levels in serum (p < .05) and brain (p < .001) while enhancing serum superoxide dismutase (SOD) activity (p < .01). Brain acetylcholinesterase (p < .01) activity and pro‐inflammatory factors in serum were also reduced. Notably, WPH‐H remodeled gut microbiota composition by increasing Dubosiella and decreasing Bacteroides and norank_f__Ruminococcaceae while stimulating SCFA production. Proteomics indicated that WPH enhanced neurotoxic Aβ autophagy, synaptogenesis, neurotransmitter delivery, and antioxidative stress response via regulated protein expression. Correlation analysis revealed strong links between modified gut microbiota, elevated SCFA levels, and hippocampal protein up‐regulation (Atg4b, Nsfl1c, Tcf20, Nr2f1, and Trappc9) and down‐regulation (Krt1). Overall, the amelioration of memory deficits in APP/PS1 mice through WPH‐H consumption can be attributed to the interconnected interactions among gut microbes, SCFAs, and brain. Our study illuminated the intricate interplay between nutrition, gut health, and memory function, emphasizing WPH's potential in alleviating AD symptoms.

Impact of antiparasitic used in livestock: effects of ivermectin spiked sediment in Prochilodus lineatus, an inland fishery species of South America.

Ivermectin (IVM) is a widely used antiparasitic. Concerns have been raised about its environmental effects in the wetlands of Río de la Plata basin where cattle have been treated with IVM for years. This study investigated the sublethal effects of environmentally relevant IVM concentrations in sediments on the Neotropical fish Prochilodus lineatus. Juvenile P. lineatus were exposed to IVM-spiked sediments (2 and 20µg/Kg) for 14days, alongside a control sediment treatment without IVM. Biochemical and oxidative stress responses were assessed in brain, gills, and liver tissues, including lipid damage, glutathione levels, enzyme activities, and antioxidant competence. Muscle and brain acetylcholinesterase activity (AChE) and stable isotopes of 13C and 15N in muscle were also measured. The lowest IVM treatment resulted in an increase in brain lipid peroxidation, as measured by thiobarbituric acid reactive substances (TBARs), decreased levels of reduced glutathione (GSH) in gills and liver, increased catalase activity (CAT) in the liver, and decreased antioxidant capacity against peroxyl radicals (ACAP) in gills and liver. The highest IVM treatment significantly reduced GSH in the liver. Muscle (AChE) was decreased in both treatments. Multivariate analysis showed significant overall effects in the liver tissue, followed by gills and brain. These findings demonstrate the sublethal effects of IVM in P. lineatus, emphasizing the importance of considering sediment contamination and trophic habits in realistic exposure scenarios.

Comparative study on biochemical responses to imidacloprid and clothianidin in cockroaches (Blattella germanica)

AbstractCockroaches, ubiquitous pests known for significant reproduction and as potential vectors of diseases, are notorious for their adoptability to a variety of insecticides that cause substantial challenges in pest control. The present research evaluated the LC50 concentrations of imidacloprid (0.65 mg/L) and clothianidin (2.5 μg/L) for Blattella germanica using topical and bait methods. The cockroaches were exposed to one‐third concentration of LC50 at a regular interval of 1, 2, 4, 8, 12, 16 and 20 days. During exposure, the activity of P450 monooxygenase increased, whereas the activity of brain acetylcholinesterase decreased. Lactate dehydrogenase, alkaline and acid phosphatase activity were highest on day 4, with a slight recovery on day 20. The elevated activities for superoxide dismutase and catalase, as well as increased lipid peroxidation levels on day 4, followed by a significant recovery in activity on day 20. The glutathione‐S‐transferase activity was elevated while the glutathione content was reduced, and a significant restoration was observed at the end of the experiment. The biochemical mechanisms of the organisms such as P450, esterase enzymes and oxidative systems, are actively involved in the detoxification mechanism. The study elucidated that the insecticide defence mechanism triggers detoxification pathways that encompass the metabolism of endogenous insecticidal compounds, with clothianidin showing greater efficacy and lower detoxification compared with imidacloprid.

Memory enhancing and neuroprotective effects of apomorphine in a rat model of dementia.

Oxidative stress from generation of increased reactive oxygen species or has been reported to play an important role in dementia. Oxidative stress due to free radicals of oxygen or reactive oxygen species could be precipitating factors in the etiology of dementia. Apomorphine has been reported to have neuroprotective effects. To monitor memory enhancing and neuroprotective effects of apomorphine, we determined the antioxidant enzymes activities, lipid peroxidation, acetylcholine esterase (AChE) activity in brain and plasma, following repetitive administration of apomorphine in rat model of dementia. Biogenic amine levels were also monitored in hippocampus. Repeated administration of scopolamine was taken as an animal model of dementia. Decreased glutathione peroxidase, superoxide dismutase and catalase activities were observed in these animal models of dementia. While increased lipid peroxidation was also observed in the brain and plasma samples. The results showed significant effects of apomorphine. The activities of antioxidant enzymes displayed increased activities in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly higher in brain and plasma of apomorphine treated rats. Superoxide dismutase (SOD) was significantly decreased in plasma of scopolamine injected rats; and a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in scopolamine treated rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM). Short-term memory and long-term memory was impaired significantly in scopolamine treated rats, which was prevented by apomorphine. Moreover, a marked decrease in biogenic amines was also found in the brain of scopolamine treated rats and was reverted in apomorphine treated rats. Results showed that scopolamine-treatment induced memory impairment and induced oxidative stress in rats as compared to saline-treated controls. These impairments were significantly restored by apomorphine administration. In conclusion, our data suggests that apomorphine at the dose of 1mg/kg could be a potential therapeutic agent to treat dementia and related disorders.

Beneficial effect of lupeol and metformin in mouse model of intracerebroventricular streptozotocin induced dementia.

This study examines the effectiveness of lupeol and metformin in a mouse model of dementia generated by intracerebroventricular streptozotocin (i.c.v., STZ). Dementia was induced in Swiss mice with the i.c.v. administration of STZ at a dosage of 3mg/kg on the first and third day. The assessment of dementia involved an examination of the Morris Water Maze (MWM) performance, as well as a number of biochemical and histological studies. STZ treatment resulted in significant decrease in MWM performance; various biochemical alterations (increase in brain acetyl cholinesterase (AChE) activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate, and reduction in nuclear factor erythroid 2 related factor-2 (Nrf-2), reduced glutathione (GSH) levels) and neuroinflammation [increased myeloperoxidase (MPO) activity & neutrophil infiltration]. The administration of Lupeol (50mg/kg & 100mg/kg; p.o.) and Metformin (150mg/kg & 300mg/kg; p.o.) demonstrated a considerable reduction in the behavioral, biochemical, and histological alterations produced by STZ. Low dose combination of lupeol (50mg/kg; p.o.) and Metformin (150mg/kg; p.o.) produced more pronounced effect than that of high doses of either agent alone. It is concluded that Lupeol and Metformin has shown efficacy in dementia with possible synergism between the two and can be explored as potential therapeutic agents for managing dementia of Alzheimer's disease (AD) type.

Protective effect of cholecalciferol against cobalt-induced neurotoxicity in rats: ZO-1/iFABP, ChAT/AchE and antioxidant pathways as potential therapeutic targets.

Cobalt (Co) toxicity has been reported to produce central nervous system and gastrointestinal abnormalities. This study assessed the therapeutic effect of cholecalciferol (Cho) supplementation against damages caused by sub-acute (14-day) cobalt chloride (CoCl2) exposure in the brain and intestines. Thirty-five male Wistar rats were divided equally into five groups: Group I (control) received no treatment; Group II received oral CoCl2 (100 mg/kg) only; Groups III, IV, and V received 1000, 3000 and 6000 IU/kg of cholecalciferol, respectively by oral gavage, and concurrently with CoCl2. Cobalt-treated rats showed neuronal vacuolation and presence of pyknotic nuclei in the cerebral cortex and hippocampus, depletion of Purkinje cells in the cerebellum, as well as inflammation and congestion in the intestinal mucosa. Cobalt also increased brain and intestinal hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations, while simultaneously reducing glutathione (GSH) content, superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities. Further, CoCl2 induced increases in brain acetylcholinesterase (AchE) activity and serum zonulin (ZO-1) levels. Conversely, Cho administration suppressed CoCl2-induced damages in the brain and intestines by reducing lipid peroxidation and increasing the activities of antioxidant enzymes. Remarkably, Cho produced stimulation of brain choline acetyltransferase (ChAT) and suppression of AchE activity, along with dose-dependent reduction in serum levels of ZO-1, intestinal fatty acid-binding protein (iFABP) and nitric oxide. In conclusion, the protective role of cholecalciferol against cobalt-induced toxicity occurred via modulation of cholinergic, intestinal permeability and antioxidant pathways. The results may prove significant in the context of the role of gut-brain connections in neuroprotection.

Lambda-Cyhalothrin induced behavioural, neurotoxic and oxidative stress on vertebrate model Danio rerio (Hamilton-Buchanan 1822).

λ-cyhalothrin, a synthetic type II pyrethroid, has become increasingly popular for control of aphids, butterfly larvae, and beetles, replacing other agricultural chemicals. As a result of which, residues of this synthetic pesticide are being reported across the globe in natural water, which poses a serious threat to aquatic life. Therefore, the present study was designed to understand the toxicity effects of λ-cyhalothrin on behaviour, oxidative stress and neurotoxicity in a vertebrate aquatic model, zebrafish (Danio rerio). The fish were exposed to 0.129, 0.194 and 0.388 µg/L corresponding to 5%, 10% and 20% of 96hLC50 (1.94 µg/L) for 28 days. Upon exposure to the highest concentration (0.388 µg/L), the test animal exhibited significant alterations in behavioural patterns like number of entries to the top zone (n), decrease in average speed (m/s) and decrease in time spent in top zone (s). Moreover, the shoaling test demonstrated a significant decrease (p < 0.05) in the relative time spent by the tested fish (%) near the stimulus fish. The change in behavioural alterations might be linked to a significant decrease (p < 0.05) in the brain acetylcholine esterase activity. Furthermore, the present study also illustrates oxidative stress exerted by λ-cyhalothrin through an increase in the production of reactive oxygen species, which is again clearly depicted by a significant increase (p < 0.05) in Superoxide dismutase, Catalase and Glutathione peroxidase activities. Overall, the present study systematically demonstrates the chronic effects of λ-cyhalothrin on adult fish behaviour and physiology, which will contribute to assessing the risks of λ-cyhalothrin to organismal health.

Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer’s disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that causes severe dementia and memory loss. Surface functionalized poly(lactic-co-glycolic acid) nanoparticles have been reported for better transport through the blood–brain barrier for AD therapy. This study investigated the improved therapeutic potential of berberine-loaded poly(lactic-co-glycolic acid)/Tet-1 peptide nanoparticles (BBR/PLGA-Tet NPs) in a rat model of sporadic AD. BBR was loaded into the PLGA-Tet conjugate. BBR/PLGA-Tet NPs were physicochemically and morphologically characterized. AD was achieved by bilateral intracerebroventricular (ICV) injection of streptozotocin (STZ). Cognitively impaired rats were divided into STZ, STZ + BBR, STZ + BBR/PLGA-Tet NPs, and STZ + PLGA-Tet NPs groups. Cognitive improvement was assessed using the Morris Water Maze. Brain acetylcholinesterase and monoamine oxidase activities, amyloid β42 (Aβ42), and brain glycemic markers were estimated. Further, hippocampal neuroplasticity (BDNF, pCREB, and pERK/ERK), Tau pathogenesis (pGSK3β/GSK3β, Cdk5, and pTau), inflammatory, and apoptotic markers were evaluated. Finally, histopathological changes were monitored. ICV-STZ injection produces AD-like pathologies evidenced by Aβ42 deposition, Tau hyperphosphorylation, impaired insulin signaling and neuroplasticity, and neuroinflammation. BBR and BBR/PLGA-Tet NPs attenuated STZ-induced hippocampal damage, enhanced cognitive performance, and reduced Aβ42, Tau phosphorylation, and proinflammatory responses. BBR/PLGA-Tet NPs restored neuroplasticity, cholinergic, and monoaminergic function, which are critical for cognition and brain function. BBR/PLGA-Tet NPs may have superior therapeutic potential in alleviating sporadic AD than free BBR due to their bioavailability, absorption, and brain uptake.

Assessing the water quality in a World Heritage Site using biomarkers in top fish predators

The use of biomarkers in fish for biomonitoring is a valuable approach to reveal effects of human impacts on biota health. Top predator fish are effective models for monitoring human activities' impacts on aquatic ecosystems. The Guaraguaçu River is the largest river-system on coastal region of South Brazil and a World Heritage site. The river receives contaminants from disorderly urban growth, including discharges of domestic sewage and small fishery boats, particularly during the tourist season. Our study aimed to assess impact of anthropogenic activities on water quality in the Guaraguaçu River by analyzing environmental contamination biomarkers in the top fish predator Hoplias malabaricus. Fish were collected using a fyke net trap across sectors representing a gradient of anthropic impact: sector 1 - pristine; sector 2 – impacted; and sector 3 - less impacted. Water samples were collected to analyze the presence of trace elements and pesticide. Biomarkers of the antioxidant system, histopathology, genotoxicity, neurotoxicity, and concentration of trace elements were analyzed in fish tissues. In water samples Al, Fe and Mn were detected, but no pesticides were found. In fish muscle, zinc and iron were detected. Brain acetylcholinesterase activity decreased in impacted sectors, indicating neurotoxic effects. The antioxidant system increased activity in gills and liver, and damage from lipoperoxidation was observed, particularly in sector 2 when compared to sector 1, suggesting oxidative stress. Histopathological biomarkers revealed lesions in the liver and gills of fish in impacted sectors. Micronuclei, a genotoxicity biomarker, were observed in organisms from all sectors. Our results demonstrate detrimental effects of poor water quality on biota health, even when contaminants are not detected in water.

Neurotoxic effects of low dose ranges of environmental metal mixture in a rat model: The benchmark approach

Metals exert detrimental effects on various systems within the body, including the nervous system. Nevertheless, the dose-response relationship concerning the administration of low doses of metal mixtures remains inadequately explored. The assessment of neurotoxic effects of lead, cadmium, mercury, and arsenic mixture (MIX) administered at low dose ranges, was conducted using an in vivo approach. A subacute study was conducted on a rat model consisting of a control and five treatment groups subjected to oral exposure with gradually increasing doses (from MIX 1 to MIX 5). The results indicated that behavioural patterns in an already developed nervous system displayed a reduced susceptibility to the metal mixture exposure with tendency of higher doses to alter short term memory. However, the vulnerability of the mature brain to even minimal amounts of the investigated metal mixture was evident, particularly in the context of oxidative stress. Moreover, the study highlights superoxide dismutase's sensitivity as an early-stage neurotoxicity marker, as indicated by dose-dependent induction of oxidative stress in the brain revealed through Benchmark analysis. The narrowest Benchmark Dose Interval (BMDI) for superoxide dismutase (SOD) activity (1e-06 - 3.18e-05 mg As/kg b.w./day) indicates that arsenic may dictate the alterations in SOD activity when co-exposed with the other examined metals. The predicted Benchmark doses for oxidative stress parameters were very low, supporting “no-threshold” concept. Histopathological alterations were most severe in the groups treated with higher doses of metal mixture. Similarly, the brain acetylcholinesterase (AChE) activity demonstrated a dose-dependent decrease significant in higher doses, while BMDI suggested Cd as the main contributor in the examined metal mixture. These findings imply varying susceptibility of neurotoxic endpoints to different doses of environmentally relevant metal mixtures, advocating for risk assessment and regulatory measures to address metal pollution and enhance remediation strategies.

Brain acetylcholinesterase activity and the protective effect of Gac fruit on scopolamine-induced memory impairment in adult zebrafish

Gac fruit (Momordica cochinchinensis) belongs to the Cucurbitaceae family. This study aimed to investigate the anti-memory impairment effect of Gac fruit aril extract and brain acetylcholinesterase activity in adult zebrafish (Danio rerio). The behavioral test was performed using a color-biased appetite conditioning T-maze test and an inhibitory avoidance test to evaluate memory performance. The time spent in the green arm in the T-maze test was recorded, and latency time was recorded in the inhibitory avoidance test. Brain acetylcholinesterase (AChE) enzyme activity was measured using a 96-well microplate reader based on Ellman's method. Zebrafish that received rivastigmine and Gac extract had significantly increased time spent in the green arm and latency time when compared to the SCO group. Zebrafish that received rivastigmine and Gac fruit extract at 200 mg/kg had lower AChE activity than the SCO groups; however, there were no statistically significant differences between the groups. These findings suggest that Gac fruit extract has anti-memory impairment activity and may be beneficial for the development of health products to prevent Alzheimer’s disease.

Oil spill in an amazon blackwater environment: Biochemical and physiological responses of local fish species

The accidental spill of petroleum asphalt cement (PAC) in São Raimundo (SR Harbor, located on the Rio Negro (Manaus, Amazonas, Brazil) was monitored through the analysis of polyciclic aromatic hydrocarbons (PAHs) in water and a set of biomarkers in fishes (exposure biomarkes: PAHs-type metabolites concentrations in bile; the activities of ethoxyresorufin-O-deethylase (EROD), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in liver. Effect biomarkers: lipid peroxidation concentration (LPO) in liver, acetylcholinesterase activity in brain, and genotoxic DNA damage in erythrocytes). Two fish species, Acarichthys heckelii and Satanoperca jurupari, were collected 10, 45, and 90 days after the PAC spill in São Raimundo. At the same time, fish were collected from the Tupé Sustainable Development Reserve (Tupé) which served as a reference area. The sampling periods were related to the rising waters of the natural flood pulse of the Rio Negro. Higher concentrations of PAHs in water were observed at 10 and 45 days and returned to the values of TP 90 days after the PAC spill, a period in which harbor waters rose about 0.2 m. Unlike the PAHs in water, biomarker responses in both fish species significantly increased following the PAC spill in SR. Hepatic ethoxyresorufin-O-deethylase (EROD), PAH-like metabolites in bile, and erythrocyte DNA damage increases, together with inhibition of acetylcholinesterase (AChE) activity in the brain were the most evident responses for both fish species. The calculated pyrolytic index showed mixed sources of PAHs (petrogenic and pyrolytic). The applied PCA-FA indicated important relationships between dissolved organic carbon (DOC) and PAHs concentrations in water, where DOC and PAHs concentrations contributed to biomarkers responses for both fish species in all collection periods.

Tiger nut/coconut dietary intervention as antidotal nutritional remediation strategy against neurobehavioural deficits following organophosphate-induced gut-brain axis dysregulation in mice

Organophosphate poisoning remains a global health crisis without efficacious treatments to prevent neurotoxicity. We examined whether antidotal tiger nut and coconut dietary intervention could ameliorate neurobehavioral deficits from organophosphate dichlorvos-induced gut-brain axis dysregulation in a mouse model. Mice were divided into groups given control diet, dichlorvos-contaminated diets, or dichlorvos plus nut-enriched diets. They were exposed to a DDVP-contaminated diet for 4 weeks before exposure to the treatment diets for another 8 weeks. This was followed by behavioural assessments for cognitive, motor, anxiety-, and depressive-like behaviours. Faecal samples (pre- and post-treatment), as well as blood, brain, and gut tissues, were collected for biochemical assessments following euthanasia. Dichlorvos-exposed mice displayed impairments in cognition, motor function, and mood along with disrupted inflammatory and antioxidant responses, neurotrophic factor levels, and acetylcholinesterase activity in brain and intestinal tissues. Weight loss and altered short-chain fatty acid levels additionally indicated gut dysfunction. However, intervention with tiger nut and/or coconut- enriched diet after dichlorvos exposure attenuated these neurobehavioral, and biochemical alterations. Our findings demonstrate organophosphate-induced communication disruptions between the gut and brain pathways that manifest in neuropsychiatric disturbances. Overall, incorporating fibre-rich nuts may represent an antidotal dietary strategy to reduce neurotoxicity and prevent brain disorders associated with organophosphate poisoning.

Dihydroxytrimethoxyflavone possess memory improvement effects against scopolamine in mice via modulating multiple pathways: In‐silico and in‐vivo evidences

AbstractBackgroundDementia is a deliberating neurodegenerative disorder which causes impairment of intellectual functions. The USFDA approved drugs has limited efficacy and numerous side effects. Thus, finding newer drugs to manage dementia and cognitive disorders is certainly required. The present study explores the potential of a natural flavone, 5,7‐dihydroxy‐3',4',5'‐trimethoxyflavone (DHF), as memory enhancer drug against scopolamine‐induced cognitive deficit in mice.MethodsAnimals were treated with DHF (5‐10 mg/kg, p.o.) for 7 days after inducing cognitive impairment by scopolamine (1mg/kg,i.p.). Memory functions (passive shock avoidance task and Morris Water Maze), brain acetylcholinesterase (AChE) activity, inflammatory markers, oxidative stress, apoptotic biomarkers and histopathological studies (H&amp;E and congo red staining for beta amyloid) were determined to measure memory improvement effects of DHF. In‐silico (molecular docking) studies were performed to understand the interactions of DHF with key pathological enzymes related to dementia.ResultsTreatment of scopolamine administered mice with DHF improved scopolamine‐induced cognitive impairment and restore brain biochemical parameters (inhibited acetylcholinesterase activity, enhanced glutathione levels, and reduced TBARS, TNF‐α, IL‐6, IL‐1β and caspase‐3 levels). Moreover, histopathological studies showed that DHF treatment reduced the neuronal cell death and amyloid depositions in mice brain. Further, molecular docking studies revealed string interactions of DHF with crucial amino acids of AChE and caspase‐3.ConclusionThese results suggest that DHF was effective in treating scopolamine induced cognitive deficit by improving cerebral cholinergic dysfunction and reducing brain oxidative stress, inflammation, apoptosis and beta‐amyloid depositions in mice. Thus, DHF could be developed as a potential alternative drug to treat memory disorders.

Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder.

Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.

Probing the multitargeting potential of n-hexane fraction of Gongronema latifolium leaves in neurodegeneration via in vitro, GC–MS and in silico studies

BackgroundNeurodegenerative disorders (NDDs) are associated with increased activities of brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) as well as Aβ-amyloid (Aβ) neurotoxicity; therefore, they offer a therapeutic option for the treatment of NDDs such as Alzheimer’s disease (AD). This study was aimed at identifying multi-targeting neurotherapeutics from Gongronema latifolium leaves using in vitro analysis, GC–MS profiling and computational methods.ResultsThe n-hexane solvent partition fraction of the methanol extract of Gongronema latifolium leaf (HF) exhibited concentration-dependent inhibitory activities against acetylcholinesterase and butyrylcholinesterase but not against MOA in vitro. The GC–MS chemical profiling identified 17 phytochemicals from the HF; these were further screened against human AChE, BChE, β-secretase enzyme (BACE1) and amyloid-β (Aβ) fibrils using molecular docking, ensemble-based docking (EBD), molecular dynamics simulation (MDs) and binding free energy (BFG) coupled with predictive adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis. The lead phytochemicals (LPs) (dihydroactinidiolide and 1H-Indole-3-ethanamine), with mean binding energies (− 6.525 ± 0.895 and 6.475 ± 0.985; − 6.833 ± 0.461 and − 6.466 ± 0.577; − 6.2 ± 0.845 and − 5.95 ± 0.353 kcal/mol) exhibited multi-target binding tendencies to the catalytic residues of hAChE, hBChE and hBACE1, in addition to hAβ fibril-disruptive tendencies (− 6.325 ± 0.545 and − 5.95 ± 0.353 kcal/mol), respectively. These results corroborated the initial molecular docking and BFG computations. The lead phytochemical–protein complexes were stable during the period of MDs. The LP presented favorable drug-likeness and ADMET properties coupled with the capacity to traverse the BBB.ConclusionDihydroactinidiolide and 1H-Indole-3-ethanamine, in part or in synergy, are identified as neurotherapeutic constituents of Gongronema latifolium that may have been responsible for the ethnopharmacologically reported neurotherapeutic activities of the leaf, and hence they are suggested as potential drug candidates that can be useful for managing or treating neurodegenerative disease such as Alzheimer's disease, subject to further investigation.

Sex-specific neurobehavioral and biochemical effects of developmental exposure to Malathion in offspring mice.

Malathion is an organophosphate pesticide (OP) commonly used in agriculture, industry, and veterinary medicine. Sex is a crucial factor in responding to neurotoxicants, yet the sex-specific effects of OP exposure, particularly neurological impairments following chronic low-level exposure remains limited. Our study aims to evaluate the neurobehavioral and biochemical effects of developmental exposure to Malathion across sexes. Pregnant mice were exposed to a low oral dose of Malathion from gestation up to the weaning of the pups, which were individually gavaged with a similar dose regimen until postnatal day 70. Our results show that Malathion decreased body weight and food intake, reduced locomotor activity and recognition memory. Motor coordination and special memory were only altered in females, whereas we found a male-specific effect of Malathion on social behavior and marble burying. These alterations were accompanied by increased malondialdehyde (MDA), decreased brain acetylcholinesterase activity (AChE), and disrupted brain redox homeostasis. Our findings about the effects of Malathion exposure across sexes may, in part, contribute to understanding the dimorphic susceptibilities observed in neurological disorders.

Omics techniques reveal the toxicity mechanisms of three antiepileptic drugs to juvenile zebrafish (Danio rerio) brain and liver

Epilepsy, a neurological disorder, is characterized by seizures that are an appearance of excessive brain activity and is symptomatically treated with antiepileptic drugs (AEDs). Oxcarbazepine (OCBZ), lamotrigine (LTG), and carbamazepine (CBZ) are widely used AEDs in clinics and are very often detected in aquatic environments. However, neither the sub-lethal effects nor the specific mechanisms of these AEDs’ action on the fish are well understood. In this study, juvenile zebrafish were exposed to a sub-lethal concentration (100 μg/L) of OCBZ, LTG, and CBZ for 28 d, after which indicators of oxidative stress (i.e. superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) level) and neurotoxicity (i.e. acetylcholinesterase (AChE) activity, γ-aminobutyric acid (GABA) level, and glutamic acid (Glu) level) were measured. Brain SOD activity was significantly increased by three AEDs, while brain CAT activity was significantly inhibited by LTG and CBZ. Liver SOD activity was significantly enhanced by CBZ, and liver CAT activity was significantly induced by OCBZ and LTG. Liver MDA level was significantly increased by three AEDs. Brain AChE activity was significantly increased by LTG and CBZ, and brain GABA level was significantly enhanced by three AEDs. However, there were no significant alterations in the levels of MDA and Glu in zebrafish brain. To ascertain mechanisms of AEDs-induced toxicity, brain transcriptomics and liver metabolomics were conducted in zebrafish. The brain transcriptomics results showed that lots of differentially expressed genes (DEGs) were enriched in the sensory system, the immune system, the digestive system, the metabolic processes, and others in three AEDs treated groups. The metabolomics data indicated dysregulation of glycerophospholipid signaling and lipid homeostasis in zebrafish liver after three AEDs exposure. The overall results of this study improve understanding of the sub-lethal effects and potential molecular mechanisms of action of AEDs in fish.