Brain Acetylcholinesterase Activity Research Articles

N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation.

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC50 = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.

The Time Profile of the Effects of Moderate Hypothermia on Synaptic Acetylcholinesterase in Rat Brain.

Hypothermia in homeotherms significantly affects the neurotransmitter systems of the brain, including the cholinergic system. The function of the brain cholinergic system during prolonged moderate hypothermia is not known yet. We studied the effects of moderate hypothermia of various durations on the activity and kinetic parameters of synaptic acetylcholinesterase in rat brain. Immediately after body temperature decrease to 30°C, the efficiency of synaptic acetylcholinesterase catalysis significantly increases due to changes in both the maximum rate of reaction (Vmax; the rate of reaction when the enzyme is saturated with substrate) and Michaelis constant (Km). However, in the dynamics of prolonged hypothermia (1-3 h), it decreases to a level of intact animals, which was associated with normalization of the kinetic parameters of the enzyme. The detected changes in the kinetic parameters of the enzyme are compensatory and can be associated with both its reversible post-translational modifications and changes in the annular lipids.

Effects of chlorpyrifos toxicity on brain, pseudobranchial neurosecretory system and swimming performance of a catfish, Heteropneustes fossilis

In the present study, it was aimed to evaluate the adverse effects of CPF on the histopathology of the optic tectum and cerebellum, pseudobranchial neurosecretory system (PNS), biochemical assays of brain tissue, and locomotory behavior in catfish, Heteropneustes fossilis. The fishes were exposed to an environmentally relevant concentration of 0.09 and 0.192 mg/L of CPF for 7, 15, and 30 d. The CPF toxicity induced degenerative changes with significantly decreased cell size, number, and nucleo-cytoplasmic (N/C) ratio of the PNS; and altered neuro-architectural pattern of optic tectum with degenerative changes in mononuclear and granular cells and necrotic variation in granular and Purkinje cells of the cerebellum. The Acetylcholinesterase (AChE) and Catalase (CAT) activity in the CPF-exposed brain was significantly decreased, whereas Superoxide dismutase (SOD) and Malondialdehyde (MDA) level was significantly increased in comparison with control. In CPF-exposed fishes, the respiratory movements and locomotory behavioral pattern like swimming speed, total distance traveled, time mobile, absolute turn angle, head: distance traveled, maximum speed were significantly decreased, whereas time immobile and time freezing episodes were significantly increased as compared to control fishes. The present study concludes that environmentally relevant concentration of CPF may induce histopathological, biochemical, physiological, and behavioral disturbances in a non-target organism, H. fossilis.

The simultaneous action of acute paradoxical sleep deprivation and hypothyroidism modulates synaptosomal ATPases and acetylcholinesterase activities in rat brain

BackgroundThyroid dysfunctions as well as sleep abnormalities are usually followed by neurological, psychiatric and/or behavioral disorders. On the other hand, changes in the brain adenosine triphosphatases (ATPases) and acetylcholinesterase (AChE) activities show significant importance in pathogenetic pathways in the evolution of numerous neuropsychiatric diseases. MethodsThis study aimed to evaluate the in vivo simultaneous effects of hypothyroidism and paradoxical sleep deprivation for 72 h on synaptosomalATPases and AChE activities of whole rat brains.In order to induce hypothyroidism, 6-n-propyl-2-thiouracil was administrated in drinking water during 21 days. The modified multiple platform method was used to induce paradoxical sleep deprivation. The AChE and ATPases activities were measured using spectrophotometric methods. ResultsHypothyroidism significantly increased the activity of Na+/K+-ATPase compared to other groups, while at the same time significantly decreased AChE activity compared to the CT and SD groups. Paradoxical sleep deprivation significantly increased AChE activity compared to other groups. The simultaneous effect of hypothyroidism and sleep deprivation reduced the activity of all three enzymes (for Na+/K+-ATPase between HT/SD and HT group p < 0.0001, SD group p < 0.001,CT group p = 0.013; for ecto-ATPases between HT/SD and HT group p = 0.0034, SD group p = 0.0001, CT group p = 0.0007; for AChE between HT/SD and HT groupp < 0.05, SD group p < 0.0001, CT group p < 0.0001). ConclusionsThe effect of simultaneous existence of hypothyroidism and paradoxical sleep deprivation reduces the activity of the Na+/K+-ATPase, ecto-ATPases, and AChE, what is different from individual effect of hypothyroidism and paradoxical sleep deprivation itself. This knowledge could help in the choice of appropriate therapy in such condition.

A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway.

The pathogenesis of Alzheimer's disease (AD) involves multiple pathophysiological processes. Oxidative stress is a major cause of AD-associated neuronal injury. The current research was designed to examine whether a novel (-)-meptazinol-serotonin hybrid (Mep-S) with potent antioxidant activity and additional inhibitory properties for acetylcholinesterase (AChE) activity could attenuate oxidative neuronal damage and cognitive deficits. In human SH-SY5Y cells, Mep-S suppressed H2O2-induced apoptosis by restoring mitochondrial membrane potential and inhibiting caspase-3 activation. Meanwhile, it attenuated oxidative stress elicited by H2O2 through lessening generation of reactive oxygen species as well as enhancing production of glutathione (GSH) and activity of superoxide dismutase (SOD). Mechanistically, Mep-S promoted nuclear translocation of a transcription factor nuclear factor E2-related factor-2 (Nrf2) in H2O2-challenged cells. This effect was accompanied by reduction in Kelch-like ECH-associated protein-1 (Keap1) levels as well as augmentation of Akt phosphorylation and expression of heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO-1). Molecular docking analysis revealed that Mep-S may disrupt the protein-protein interactions between Keap1 and Nrf2. In an in vivo mouse model, Mep-S attenuated scopolamine-caused cognitive deficits with inhibition of apoptotic neuronal death and brain AChE activity. Furthermore, the scopolamine-induced impairment of total antioxidant capacity and reduction in SOD1, SOD2, and γ-glutamate-cysteine ligase expression in the brain were counteracted by Mep-S, accompanied by decreased Keap1 levels, increased Akt catalytic subunit and Nrf2 phosphorylation, and decreased Nrf2, HO-1, and NQO-1 expression. Collectively, our results suggest that Mep-S ameliorates apoptotic neuronal death and memory dysfunction associated with oxidative stress by regulating the Nrf2/antioxidant enzyme pathway through inactivating Keap1 and phosphorylating Nrf2 via Akt activation. Therefore, Mep-S may be a potential lead for multitarget neuroprotective agents to treat AD-like symptoms.

Comparative investigation of analgesic tolerance to taurine, sodium salicylate and morphine: Involvement of peripheral muscarinic receptors

Nowadays various analgesic medications are used for the management of acute and chronic pain. Among these opioid and non-steroidal anti-inflammatory drugs stand in the first line of therapy, however, prolonged administration of these substance is generally challenged by development of analgesic tolerance in patients. Therefore, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. In this respect, Taurine, a free amino acid, has been shown to induce significant analgesia at both spinal and peripheral levels through cholinergic mechanisms. In the present study, we used hot-plate analgesic test to investigate how taurine either as a single medication or in combination with sodium salicylate and morphine may affect both acute response to pain and development of analgesic tolerance. The effect of taurine was also tested on morphine withdrawal syndrome. Hyoscine butyl bromide was used to assess the role of muscarinic receptors in taurine-mediated effects. Finally, biochemical assay was done to reveal how the activity of brain acetylcholinesterase may change in relation with muscarinic receptor activity. Results indicated that acute administration of taurine-sodium salicylate combination causes more potent analgesia compared to the use of tau (but not SS alone) and this seems to be mediated via activity of muscarinic receptors in peripheral nervous system. Furthermore, the effect of this combination undergoes less analgesic tolerance during time. Combination of taurine and morphine is an effective strategy to attenuate both morphine analgesic tolerance and dependence and this also seems to depend on activity of muscarinic receptors, however through differential cellular mechanisms.

ВЛИЯНИЕ МЕДИ В СУБЛЕТАЛЬНЫХ КОНЦЕНТРАЦИЯХ И ТЕРМАЛЬНОГО СТРЕССА НА ФИЗИОЛОГО-БИОХИМИЧЕСКИЕ ПОКАЗАТЕЛИ МОЛОДИ ПЛОТВЫ RUTILUS RUTILUS

The effects of 7- and 14-day exposure to water-dissolved Cu at sublethal concentrations 0.01 and 0.1 mg/L and subsequent increase in water temperature at a rate of 8°C/h on intestinal proteolytic activity (PA) and amylolytic activity (AA), as well as brain acetylcholinesterase (AChE) activity and water-soluble protein (WSP) content in juvenile roach Rutilus rutilus have been in vivo studied. Additionally, the values of upper sublethal temperature were determined by the critical thermal maximum (CTM) method. The average values of the CTM (27.5°C) did not differ in fish of control (exposure to 0 μg/L Cu) and Cu-exposed groups. After Cu exposure AA was 22–34% lower, PA was 57–64% lower at Cu concentration 0.01 mg/L, but 27–35% higher at Cu concentration 0.1 mg/L. Subsequent temperature stress did not change the response of proteinases and glycosidases to Cu. An increase in water temperature decreased AA by 21%, AChE activity by 24% in fish of the control group; but increased PA by 32%. AChE activity was 24–28% lower than the control after exposure to Cu (0.1 mg/L and short-term thermal load increased the inhibitory effect of Cu. An increase of WSP content by 36–58% was revealed only after 7 days of exposure to Cu, while temperature stress did not change of the effect. In general, Cu at concentrations found in the aquatic environment can reduce the activity of digestive hydrolases in the intestines of juvenile roach, reducing the rate of assimilation of protein and carbohydrate food components. Inhibition of brain AChE activity is enhanced by subsequent temperature stress. No significant differences were noticed in CTM values in fish of control and Cu-exposed group. The results obtained are important in assessing the environmental risks of chronic exposure to Cu in the zones of thermal pollution of water bodies.

Tissue-specific accumulation, depuration, and effects of perfluorooctanoic acid on fish: Influences of aqueous pH and sex

Perfluorooctanoic acid (PFOA) is widely distributed in nature, particularly in aquatic environments. Its bioaccumulation and toxicity in aquatic organisms can be affected by both the chemical status of PFOA in water and the physiology of the organism. However, research on the patterns of these effects is scarce. In this study, we investigated the influence of aqueous pH (pH 6, acidic; pH 7.5, neutral; pH 9, basic) and fish sex on PFOA uptake, clearance, and biochemical effects in crucian carp (C. auratus) using flow-through exposure. In the 17-d kinetic experiment, PFOA bioaccumulation adhered to a uniform first-order model in which PFOA uptake rates from water to blood and liver in acidic conditions were faster than those in other conditions, indicating possible acidic pH influence on PFOA uptake. PFOA clearance rates in these compartments of males were slower than in females, which was attributed to the notably stronger expression of Oat2 (organic anion transporter 2, responsible for reabsorption) in the kidneys of males. Similar responses were observed for peroxisome proliferation-related biomarkers at different pH levels and in different sexes. These biochemical responses were driven by the internal concentrations of PFOA. The inhibition acetylcholinesterase activity in the fish brain was closely linked to changes in P-glycoprotein content, demonstrating a protective relationship. Collectively, an aqueous pH lower than 7.5 might affect the uptake of PFOA by fish. The clearance discrepancies between the sexes highlight the importance of anion carriers for ionizable organic compounds in aquatic organisms.

In silico screening, TLC bioautography and in vivo studies of Zanthoxylum armatum DC. (Indian Prickly Ash) extract as a potential neuroprotective agent

Zanthoxylum armatum DC., a popular spice, and folklore medicine, is widely distributed throughout the Northeastern region of India and practiced by indigenous tribes as a remedy for digestive and nervous system disorders. The study aimed to assess the neuro-protective potentiality of Zanthoxylum armatum extract through different learning and memory paradigms against scopolamine-induced cognitive impairment. For the isolation of the compounds, coarsely powdered shade-dried fruits were extracted with ethanol by the cold maceration method. In silico studies were performed for the isolated compounds. TLC bioautographic enzyme assay was developed to screen acetylcholinesterase and butyrylcholinesterase inhibition by plant extract using donepezil, a known acetylcholinesterase inhibitor. Memory retention activities of ethanolic extract (100, 200, and 400 mg/kg; p.o.) were determined in-vivo , along with an estimation of whole-brain cholinesterase and antioxidant activity. Chromatographic analysis from chloroform fraction resulted in the isolation of three bio-active phytoconstituents, and structural elucidation identified them as β-sitosterol (ZA-01), Stigmasterol (ZA-02), and Lupeol (ZA-03). In silico molecular docking studies revealed stigmasterol has the minimum binding energy with acetylcholinesterase among all the isolated bioactive. The stability of the protein-ligand complex was found satisfactory after performing molecular dynamics simulation studies. Pre-treatment with extract significantly improved transfer latency in maze tests decreased rat brain acetylcholinesterase activity, and showed antioxidant potentiality against scopolamine-induced memory impairment. The combination of neuroprotective, anticholinesterase, and antioxidant effects shown by Z. armatum extract may be what makes it a nootropic drug. These are good signs for the search for natural nootropics from Z. armatum extract. Even so, more research with extracts and isolated compounds will be needed to make the traditional uses of the plant more scientifically sound. • Zanthoxylum armatum is evaluated for its potential as neuroprotective agent. • β-sitosterol, Stigmasterol and Lupeol were isolated from the plant extract. • In silico molecular docking and molecular dynamics simulations were performed. • TLC bioautography, in vivo animal tests showed good neuroprotective action of Zanthoxylum armatum extract.

Potential biomarker of phenol toxicity in freshwater fish C. mrigala: Serum cortisol, enzyme acetylcholine esterase and survival organ gill

In this modern industrialized era of large-scale production of agrochemicals, various emerging contaminants form the main components of waste water and sludge in most of the developing countries of the world. In this concern, phenol- an inevitable and alarming chemical pollutant in aquatic ecosystem, gains a speedy access into the water bodies as an industrial by-product. Though the detrimental effects of phenol have been studied in various aspects of aquatic life, current study is an initiative to unravel the toxic effects of phenol at molecular level in Cirrhinus mrigala. Plasma cortisol level and acetylcholine esterase activity in fish was estimated by Chemiluminescent immunoassay technique and Ellman assay respectively. Scanning electron microscopic studies were carried out to unravel the gill histopathological alterations in exposed fish. It was observed that phenol (22.32 mg/l) inhibits 50 % of acetylcholine esterase activity in brain thereby affecting the locomotion of the targeted carp. Cortisol elevated during the 7th day in exposed fish, but declined progressively on the forthcoming 21st and 28th days. Manifestations in gill encompass curling, fusion, aberrations, sloughing of gill epithelium, wider inter filamentary space and mucus coating in the primary gill filament. It concludes that the discernable deviations produced in both biochemical parameters and key organ gill can be used as a biomarker and bio-indicator respectively for assessing the existence of emerging toxicants in aquatic ecosystem.

The mechanistic basis for the toxicity difference between juvenile rats and mice following exposure to the agricultural insecticide chlorpyrifos

At high exposure levels, organophosphorus insecticides (OPs) exert their toxicity in mammals through the inhibition of brain acetylcholinesterase (AChE) leading to the accumulation of acetylcholine in cholinergic synapses and hyperactivity of the nervous system. Currently, there is a concern that low-level exposure to OPs induces negative impacts in developing children and the chemical most linked to these issues is chlorpyrifos (CPF). Our laboratory has observed that a difference in the susceptibility to repeated exposure to CPF exists between juvenile mice and rats with respect to the inhibition of brain AChE. The basis for this difference is unknown but differences in the levels of the detoxification mechanisms could play a role. To investigate this, 10-day old rat and mice pups were exposed daily for 7 days to either corn oil or a range of dosages of CPF via oral gavage. Four hours following the last administration of CPF on day 16, brain, blood, and liver were collected. The inhibition of brain AChE activity was higher in juvenile rats as compared to juvenile mice. The levels of activity of the detoxification enzymes and the impact of CPF exposure on their activity were determined in the two species at this age. In blood and liver, the enzyme paraoxonase-1 (PON1) hydrolyzes the active metabolite of CPF (CPF-oxon), and the enzymes carboxylesterase (CES) and cholinesterase (ChE) act as alternative binding sites for CPF-oxon removing it from circulation and providing protection. Both species had similar levels of PON1 activity in the liver and serum. Mice had higher ChE activity in liver and serum than rats but, following CPF exposure, the percentage inhibition was similar between species at an equivalent dosage. Even though rats had slightly higher liver CES activity than mice, the level of inhibition following exposure was higher in rats. In serum, juvenile mice had an 8-fold higher CES activity than rats, and exposure to a CPF dosage that almost eliminated CES activity in rats only resulted in 22% inhibition in mice suggesting that the high serum CES activity in mice as compared to rats is a key component in this species difference. In addition, there was a species difference in the sensitivity of CES to inhibition by CPF-oxon with rats having a lower IC50 in both liver and serum as compared to mice. This greater enzyme sensitivity suggests that saturation of CES would occur more rapidly in juvenile rats than in mice, resulting in more CPF reaching the brain to inhibit AChE in rats.

Anti-amnesic and anti-cholinesterase activities of α-asarone against scopolamine-induced memory impairments in rats.

Alzheimer's disease (AD) is a neurological ailment that causes memory loss and impairments and is linked to a drop-in acetylcholine level. Acetylcholinesterase (AChE) inhibitors are used for the management of AD. In our ongoing research to search for natural AChE inhibitors from medicinal plants, we found that the Acorus calamus possesses memory-enhancing properties. α-Asarone is the major compound isolated from the Acorus calamus and it has neuroprotective action in animal models, nonetheless, its anticholinesterase activity in different brain regions was not fully understood. The purpose of this research was to determine the anti-amnesic and anti-cholinesterase activities of α-asarone against scopolamine-induced memory impairments in rats. The anti-cholinesterase activity of α-asarone was determined using Ellman's method in different brain areas, such as the cortex, hippocampus, and striatum. In addition, the anti-amnesic effect of α-asarone was also investigated using elevated plus-maze, passive avoidance, and active avoidance tests. The effect of α-asarone on memory impairment against scopolamine-induced (1 mg/kg body weight) amnesia was evaluated. Administration of α-asarone (15 and 30 mg/kg body weight) for 14 days to rats significantly ameliorated the scopolamine-induced memory impairment as measured in the elevated plus-maze, passive avoidance, and avoidance active tests compared to the scopolamine-treated group. In this study, we also show that α-asarone treatment significantly (p<0.05) reduced brain acetylcholinesterase activity in the cortex, hippocampus, and striatum brain regions of amnesic rats. These results confirmed that α-asarone has anti-amnesic and anti-cholinesterase potential which may be useful for the management of AD.

New Myrtenal-Adamantane Conjugates Alleviate Alzheimer's-Type Dementia in Rat Model.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal–adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer’s models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs’ neuroprotective properties in dementia. Methods: Scopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed. Results: M derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus. Conclusion: For the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.

Toxicity Profiles of Kleeb Bua Daeng Formula, a Traditional Thai Medicine, and Its Protective Effects on Memory Impairment in Animals.

Kleeb Bua Daeng (KBD) formula has long been used in Thailand as a traditional herbal medicine for promoting brain health. Our recent reports illustrated that KBD demonstrates multiple modes of action against several targets in the pathological cascade of Alzheimer’s disease (AD). The main purpose of the present study was to determine the protective effect and mechanism of KBD in amyloid beta (Aβ)-induced AD rats and its toxicity profiles. Pretreatment with the KBD formula for 14 days significantly improved the short- and long-term memory performance of Aβ-induced AD rats as assessed by the Morris Water Maze (MWM) and object-recognition tests. KBD treatment increased the activities of the antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase; reduced the malondialdehyde content, and; decreased the acetylcholinesterase activity in the rat brain. An acute toxicity test revealed that the maximum dose of 2000 mg/kg did not cause any mortality or symptoms of toxicity. An oral, subchronic toxicity assessment of KBD at doses of 125, 250, and 500 mg/kg body weight/day for 90 days showed no adverse effects on behavior, mortality, hematology, or serum biochemistry. Our investigations indicate that KBD is a nontoxic traditional medicine with good potential for the prevention and treatment of AD.

P-Coumaric acid protects against D-galactose induced neurotoxicity by attenuating neuroinflammation and apoptosis in mice brain.

D-galactose (D-gal) induced senescence in rodents is a widely used model for assessment of molecules affecting brain ageing. Chronic administration of D-gal causes neuroinflammation leading to cognitive deficit and memory impairment which represent Alzheimer's dementia. In present study, we investigated the neuroprotective effects of the natural phenol, p-Coumaric acid (PCA) and its underlying mechanism in the chronic D-gal treated mice. Subcutaneous administration of D-gal (150mg/kg) to Swiss albino mice for 42 consecutive days resulted in cognitive impairment as observed in Morris water maize (MWM) and Y maze test, which was ameliorated by concurrent treatment with PCA (80mg/kg, and 100mg/kg, p.o.). Importantly, PCA treatment attenuated the D-gal induced oxidative stress and significantly inhibited acetylcholinesterase (AChE) activity in mice brain. Furthermore, PCA treatment significantly lowered levels of inflammatory marker nuclear factor kappa B (NFκB) and reduced levels of proapoptotic enzyme caspase3. We also observed that PCA treatment exhibited β-secretase enzyme (BACE1) inhibitory effect. However, our results revealed that PCA treatment failed to decrease the level of advanced glycation end products both in vitro and in vivo. Taken together, current study demonstrated the significant neuroprotective effect of PCA against D-gal induced oxidative stress, neuroinflammation, cognitive impairment and apoptosis.

Reversal of cisplatin triggered neurotoxicity by Acacia hydaspica ethyl acetate fraction via regulating brain acetylcholinesterase activity, DNA damage, and pro-inflammatory cytokines in the rodent model

BackgroundCisplatin (CisPT) is a chemotherapeutic that outcome in adverse effects including neurotoxicity. We examined the efficacy of hydaspica ethyl acetate extract (AHE) against CisPT-prompted neurotoxicity.MethodsGroup I: Distilled water; Group II: CisPT (12 mg/kg b.w. i.p) on the 13th day of treatment. Group III: received AHE (400 mg/kg b.w) orally for 16 days. Group IV and V received 200 and 400 mg/kg b.w AHE orally for 16 days while CisPT injection on day 13, respectively. Group VI: received Silymarin (100 mg/kg b.w) orally for 16 days and CP (12 mg/kg b.w., i.p.) on day 13. TNF-α, IL6, brain acetylcholinesterase activity (AChE), oxidative trauma markers, genotoxicity, antioxidant enzymes, and morphological alterations in cerebral hemispheres were inspected.ResultsAHE administration before CisPT considerably reduced both tissue TNF-α and IL 6 expressions compared to CisPT treated group in a dose-dependent manner. AHE treatment (400 mg/kg b.w) significantly ameliorated brain AChE activity. Brain tissue MDA, H2O2, and NO content were markedly (p < 0.001) elevated after CisPT inoculation while a noticeable (p < 0.001) diminution was observed in AHE treatment groups. AHE treatment significantly (p < 0.001) improved brain antioxidant defense in a dose-dependent manner. Furthermore, AHE efficiently recused CisPT to induce DNA damage in brain tissue as revealed by ladder assay and DNA fragmentation patterns. Histopathological findings revealed severe neurodegenerations in CisPT treated group, however, AHE treatment noticeably precluded morphological alterations and neuron damages induced by CisPT.ConclusionA. hydaspica AHE extract may be provided as a prospective adjuvant that precludes CisPT-induced neurotoxicity due to its radical scavenging and antioxidant potential.

Toxic effects of waterborne benzylparaben on the growth, antioxidant capacity and lipid metabolism of Nile tilapia (Oreochromis niloticus).

Benzylparaben (BzP) is a potential endocrine disruptor; however, its antioxidant defense, lipotoxicity and underlying mechanism of BzP in aquatic organisms are unknown. This study investigated the impacts of waterborne low-, environmental-related and high-level benzylparaben on the growth, antioxidant capacity, lipid metabolism and lipidomic response of Nile tilapia (Oreochromis niloticus). Juvenile tilapia (0.60±0.11g) were exposed to 0, 5, 50, 500 and 5000ng/L benzylparaben for 8 weeks in quadruplicate for each group. Benzylparaben increased the body crude fat content but decreased brain acetylcholinesterase activity in O. niloticus. Benzylparaben caused oxidative stress, leading to hepatic morphology damage and lipid metabolism disorders in fish. Lipidomic analysis identified 13 lipid classes in fish liver. Benzylparaben exposure induced metabolic disorders of glycerol phospholipids, glycerolipids and sphingomyelins in fish liver. These findings indicate that environmentally related benzylparaben levels (5 to 50ng/L) could induce an antioxidant response, result in triglyceride accumulation, and increase adipocyte formation and fatty acid intake in tilapia. However, high benzylparaben concentrations inhibit lipid deposition, presumably due to the effects of the antioxidant system, and induce tissue inflammation. Therefore, this study provides new insights into the toxic effects and potential mechanism of benzylparaben in fish, especially from the aspect of lipid metabolism.

Trimethoxyflavones from Ocimum basilicum L. leaves improve long term memory in mice by modulating multiple pathways

Ethnopharmacological relevanceTraditionally, Ocimum basilicum L. leaves (OB) are recommended for various brain disorders. Aim of the studyScientific evidence highlights the cognition improvement capacity of Ocimum basilicum L. leave extract (OBE), however, the compound(s) responsible for this effect and the associated mechanism was not reported. The present study was, thus, designed to isolate and identify the compound responsible for memory improvement effects of OB and to delineate the associated mechanism of action. Materials and methodsIn-vitro acetylcholinesterase (AChE) inhibitory (Ellman method) and antioxidant (DPPH scavenging) assays guided fractionation was employed to isolate the bioactive compounds from OBE. The isolated compounds were characterised using spectroscopic techniques (FTIR, NMR and MS). In-silico and in-vivo [mouse model of scopolamine (SCOP) induced amnesia] investigations were used to substantiate the memory improvement effects of isolated compounds and to understand their mechanism of action. ResultsAChE and DPPH assays guided fractionation of OBE lead to isolation of two pure compounds namely, 5,7-dihydroxy-3′,4′,5′-trimethoxyflavone (S1) and 3-hydroxy-3′,4′,5′-trimethoxyflavone (S2). Both S1 and S2 mitigated the cognitive impairment due to SCOP in mice by reducing brain AChE activity, TBARS, TNF-α, IL-1β, IL-6 and caspase-3 concentrations and elevating reduced glutathione and IL-10 levels; together with amelioration of brain hippocampus histopathological aberration (H and E staining). Moreover, the molecular docking of S1 and S2 at the active pockets of AChE and caspase-3 has shown good interactions with vital amino acid residues. ConclusionsOur findings show that trimethoxy flavones are responsible for the memory improvement effect of OBE due to their anticholinergic, antioxidant, anti-inflammatory and anti-apoptotic properties. These maybe developed as valuable alternatives for management of cognitive disorders.

Phospholipids modifications, genotoxic and anticholinesterase effects of pepper fruit (Dennettia tripetala G. Baker) extract in Swiss mice

The toxicity of D. tripetala fruit extract to mice was investigated using data obtained from lipidomic analyses, comet and Acetylcholinesterase (AChE) assays. Mice (n = 8) were exposed for 30 days via oral gavage to vehicle (5% Tween 80) (negative control), D. tripetala extract (100, 200 and 400 mg/kg) and 40 mg/kg methyl methanesulfonate (MMS) (positive control). The profile of compounds in the fruit extract was analyzed using gas chromatography-mass spectrometry. Out of the total of 32 compounds identified, considerable amount of established insecticidal compounds such as 2-phenylnitroethane, cis-vaccenic acid, linalool and linoleic acid were detected. Fruit extract did not induce DNA damage relative to negative control. Percentage gain in body weights differed significantly across the four weeks. Significantly highest and lowest brain AChE activity was observed in animals exposed to 200 and 400 mg/kg D. tripetala, respectively. Fruit extract modulated the brain phospholipid profile due to significant fold changes of 48 lipid species out of the total of 280 lipid species. High number of differentially expressed phosphatidylcholine (PC) species and significant levels of phosphatidylethanolamine (PE) at 400 mg/kg suggests that activation of inflammation and methylation pathways are the most plausible mechanisms of D. tripetala toxicity to mouse brain tissue.

Inhibition of Serum Esterases in Juvenile Rats Repeatedly Exposed to Low Levels of Chlorpyrifos.

Chlorpyrifos (CPF) is an organophosphorus insecticide that has gained significant attention cue to the reported toxicity associated with developmental exposure. While the canonical mechanism of toxicity of CPF involves the inhibition of brain acetylcholinesterase (AChE), we have reported that exposure of juvenile rats to levels of CPF that do not yield any inhibition of brain AChE results in neurobehavioral alterations at later ages. However, it is unclear what effect exposure to these low levels of CPF has on blood esterase activities which are frequently used not only as biomarkers of exposure but also to set exposure levels in risk assessment. To determine this, male and female rat pups were exposed orally from postnatal day 10 to 16 to either corn oil (vehicle) or 0.5, 0.75, or 1.0 mg/kg CPF. At 12 h after the final exposure, serum cholinesterase (ChE), butyrylcholinesterase (BChE), and carboxylesterase (CES), and red blood cell (RBC) and brain AChE activities were determined. There were no differences between sexes in either the controls or individual treatments for all enzymes. Only the highest dosage of 1.0 mg/kg CPF yielded significant brain AChE inhibition (22-24%) but all dosages significantly inhibited the blood esterases with inhibition being highest with serum CES (65-85%) followed by serum BChE (57-76%), RBC AChE (35-65%), and then serum ChE (16-32%). Our data verify that blood esterases are inhibited at dosages of CPF that alter neurobehavioral performance in the absence of effects on brain AChE activity.