Flaxseed Oil as a Neuroprotective Agent on Lead Acetate-Induced Monoamineric Alterations and Neurotoxicity in Rats

Lead remains a considerable occupational and public health problem, which is known to cause a number of adverse effects in both man and animals. Here, the neuroprotective effect of flaxseed oil (1,000 mg/kg) on lead acetate (20 mg/kg) induced alternation in monoamines and brain oxidative stress was examined in rats. The levels of lead, dopamine (DA), norepinephrine (NE), serotonin (5-HT), lipid peroxidation, nitrite/nitrate (NO), and glutathione (GSH) were determined; also, the activity of acetylcholinesterase (AChE) and Na(+)-K(+)-ATPase were estimated on different brain regions of adult male albino rats. The level of lead was markedly elevated in different brain regions of rats. This leads to enhancement of lipid peroxidation and NO production in brain with concomitant reduction in AChE activity and GSH level. In addition, the levels of DA, NE, and 5-HT were decreased in the brain. These findings were associated with BAX over expression. Treatment of rats with flaxseed oil induced a marked improvement in most of the studied parameters as well as the immunohistochemistry features. These data indicated that dietary flaxseed oil provide protection against lead-induced oxidative stress and neurotoxic effects.     

The Effects of Flaxseed Oil on Cadmium-Induced Oxidative Stress in Rats

In the present study, the effects of flaxseed oil on the oxidant–antioxidant system in cadmium intoxication were investigated in rats. Forty-eight male Wistar albino rats were divided into four equal groups (group 1). No treatment was applied to the control group. On the other hand, groups 2, 3, and 4 were administered with 0.1 ml/rat/day (～500 mg/kg bw) flaxseed oil by gavage into the stomach, 50 ppm of cadmium (～4 mg/kg bw) in ad libitum drinking water, and 0.1 ml/rat/day flaxseed oil plus 50 ppm of cadmium, respectively, for 30 days. At the end of the study, malondialdehyde and nitric oxide levels and catalase, superoxide dismutase, and glutathione peroxidase activities were measured in blood and tissue (liver, lung, kidney, brain, heart, and testes) samples. While malondialdehyde and nitric oxide levels increased in the group given cadmium compared to the control group; in the meantime, there were some significant changes in antioxidant enzyme activities. These changes were observed, the trends of decrease or increase compared to the control group. There were positive changes in parameters of the group given with flaxseed oil plus cadmium compared to the group receiving cadmium alone, in other words, values were seen coming close to control group. As a result, cadmium exposure caused oxidative damage to erythrocytes and organs at varying rates, while flaxseed oil reduced the severity of cadmium-induced lipid peroxidation. Therefore, it was concluded that flaxseed oil can be used among compounds as a therapeutic agent or food additive for prophylaxis in cadmium intoxication.     

The Redox Status in Rats Treated with Flaxseed Oil and Lead-Induced Hepatotoxicity

Lead is a persistent environmental pollutant, and its toxicity continues to be a major health problem due to its interference with natural environment. In the present study, we have evaluated the effect of flaxseed oil on lead acetate-mediated hepatic oxidative stress and toxicity in rats. Lead acetate enhanced lipid peroxidation and nitric oxide production in both serum and liver with concomitant reduction in glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase activities, these findings were associated with DNA fragmentation. In addition, lead acetate caused liver injury as indicated by histopathological changed of the liver with an elevation in total bilirubin, serum alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, and alkaline phosphatase. Treatment of rats with flaxseed oil resulted in marked improvement in most of the studied parameters as well as histopathological features. On the basis of the above results it can hypothesized that flaxseed oil is a natural product can be protect against lead acetate-mediated hepatic cytotoxicity.     

Molecular Mechanisms of Lead Neurotoxicity

Epidemiological studies have shown a strong relationship between the level of lead in blood and bone as assessed by performance on IQ tests and other psychometric tests. Approximately 1 out of 10 children in the United States have blood lead levels above 10g/dl, which has been established as the level of concern. Studies on experimental animals exposed to lead after birth have shown learning deficits at similar blood lead levels. Since learning requires the remodeling of synapses in the brain, lead may specifically affect synaptic transmission. Although the molecular targets for lead are unknown, a vast amount of evidence accumulated over many years has shown that lead disrupts processes that are regulated by calcium. Our laboratory has been studying the effect of lead on protein kinase C, a family of isozymes some of which require calcium for activity. We and others have shown that picomolar concentrations of lead can replace micromolar concentrations of calcium in a protein kinase C enzyme assay. Furthermore, lead activates protein kinase C in intact cells and induces the expression of new genes by a mechanism dependent on protein kinase C. We propose that the learning deficits caused by lead are due to events regulated by protein kinase C that most likely occur at the synapse.     

硒对铅暴露致神经损伤的拮抗作用研究

目的:研究铅暴露诱导的神经毒性损伤作用,明确铅暴露引发神经毒性损伤的部分机制以及硒的保护作用。方法:通过哺乳期染铅及补充硒建立铅暴露动物模型;通过TUNEL实验确定铅暴露引发的神经损伤;通过Western blot实验检测Bax、Bcl-2、Caspase-3水平确定铅暴露对凋亡途径的启动;并确证补硒在铅神经毒性作用下对机体的保护作用。结果:1.哺乳期铅暴露能够引起仔鼠海马神经细胞凋亡的发生;2.铅暴露能够诱导Bax/Bcl-2水平改变,激活Caspase-3。3.同时给予硒干预后,机体抗铅神经毒性能力显著增加。结论:1.铅暴露能够诱导海马部位神经毒性损伤,损伤可能通过启动凋亡途径而发生,2.补硒能够通过拮抗凋亡发生从而拮抗铅的神经毒性,产生保护作用。     

Presynaptic Mechanisms of Lead Neurotoxicity: Effects on Vesicular Release,Vesicle Clustering and Mitochondria Number

Childhood lead (Pb²⁺) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb²⁺ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb²⁺ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb²⁺ neurotoxicity, we show that Pb²⁺ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb²⁺ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development.     

Gelled Double-Layered Emulsions for Protection of Flaxseed Oil

Multilayer systems may present different functional properties according to the number of layers deposited, the type of biopolymers, the sequence of biopolymer layers, and the solution properties used during deposition. In this study, gelatin-stabilized emulsions were coated with alginate in order to produce double-layered emulsions. Concentrations of both primary emulsion and alginate in the outer layer were evaluated by a stability map. Results indicated the occurrence of depletion flocculation in emulsions with lower gelatin concentration due to excess of alginate. Stable emulsions were atomized in a calcium chloride solution for producing microgels, which resulted in semi-rounded monomodal particles. Emulsification process promoted a reduction in the content of the secondary oxidation products of flaxseed oil as compared to non-emulsified oil, while the gelation process was responsible for a considerable improvement on oxidative stability with significant reduction on both primary and secondary oxidation products during storage. These lipid-based microgels could be potentially used as delivery systems with improved oxidative stability.     

Effect of Grape Seed Proanthocyanidin Extracts on Methylmercury-Induced Neurotoxicity in Rats

As a highly toxic environmental pollutant, methylmercury (MeHg) can cause neurotoxicity in animals and humans. Considering the antioxidant property of grape seed proanthocyanidin extracts (GSPE), this study was aimed to evaluate the effect of GSPE on MeHg-induced neurotoxicity in rats. Rats were exposed to MeHg by intraperitoneal injection (4, 12 μmol/kg, respectively) and GSPE was administered by gavage (250 mg/kg) 2 h later. After a 4-week treatment, phosphate-activated glutaminase, glutamine synthetase, glutathione peroxidase and superoxide dismutase activities, glutamate, glutamine, malondialdehyde and glutathione contents in cerebral cortex were measured. Reactive oxygen species (ROS) and apoptosis were also estimated in cells. The results showed that the MeHg-induced neurotoxicity was significantly attenuated. GSPE significantly decreased the production of ROS, counteracted oxidative damage and increased the antioxidants and antioxidant enzymes activities in rats prior to MeHg exposure. Moreover, the effects on the rate of apoptotic cells and the disturbance of glutamate homeostasis were correspondingly modulated. These observations highlighted the potential of GSPE in offering protection against MeHg-induced neurotoxicity.     

锌对铅染毒新生大鼠成骨细胞增殖分化的影响

目的:探讨铅锌联合染毒对乳鼠颅骨成骨细胞增殖分化的影响。方法:分离并培养原代成骨细胞,加入不同浓度铅、锌培养48h,检测其对成骨细胞增殖的作用;用碱性磷酸酶试剂盒检测ALP活力。结果:在染铅48h后,当铅浓度≥10μmol/L时,细胞增殖功能下降(P<0.05);加锌干预48h后,铅+锌组细胞增殖功能均高于各自单独染铅组,其中铅(1μmol/L、10μmol/L)+锌(50μmol/L)组、铅(10)+锌(100)组与对照组间的差异具有统计学意义(P<0.05)。铅干预48h后,100μmol/L铅组的ALP活力显著下(P<0.05),给予锌干预的铅锌联合染毒组,各组ALP活力均有增加,其中铅(1μmol/L、10μmol/L)+锌(50μmol/L)组ALP活力均高于对照组,而铅(100μmol/L)+锌(50μmol/L)组ALP活力低于对照组,差异均有统计学意义(P<0.05)。结论:铅对成骨细胞有毒性作用,影响其增殖和分化功能;50μmol/L锌在一定程度上可以拮抗铅对成骨细胞增殖和分化功能的损伤,且对ALP活力的作用更显著,为铅中毒骨病的防治提供一定的科学依据。     

Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats

Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50–60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood–brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.     

Dietary Flaxseed Oil Supplementation Mitigates the Effect of Lead on the Enzymes of Carbohydrate Metabolism, Brush Border Membrane, and Oxidative Stress in Rat Kidney Tissues

Lead is a heavy metal widely distributed in the environment. Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Human and animal exposure demonstrates that lead is nephrotoxic. However, attempts to reduce lead-induced nephrotoxicity were not found suitable for clinical use. Recently, flaxseed oil (FXO), a rich source of ω-3 fatty acids and lignans, has been shown to prevent/reduce the progression of certain types of cardiovascular and renal disorders. In view of this, the present study investigates the protective effect of FXO on lead acetate (PbAc)-induced renal damage. Rats were pre-fed normal diet and the diet rich in FXO for 14 days, and then, four doses of lead acetate (25 mg/kg body weight) were administered intraperitoneally while still on diet. Various serum parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), and oxidative stress were analyzed in rat kidney. PbAc nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. PbAc increased the activities of lactate dehydrogenase and NADP-malic enzyme, whereas it decreased malate and glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and BBM enzyme activities. PbAc caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased activities of superoxide dismutase, glutathione peroxidase, and catalase. In contrast, FXO alone enhanced the enzyme activities of carbohydrate metabolism, BBM, and antioxidant defense system. FXO feeding to PbAc-treated rats markedly enhanced resistance to PbAc-elicited deleterious effects. In conclusion, dietary FXO supplementation ameliorated PbAc-induced specific metabolic alterations and oxidative damage by empowering antioxidant defense mechanism and improving BBM integrity and energy metabolism.     

Protective Effect of FTY720 Against Sevoflurane-Induced Developmental Neurotoxicity in Rats

Sevoflurane, a common used inhaled anaesthetic, induces neuronal apoptosis in preclinical studies and correlates with functional neurological impairment. We investigated whether FTY720, a known sphingosine-1 phosphate (S1P) receptor agonist, could exert neuroprotective effect against sevoflurane-induced neurotoxicity. Neuroprotective effect of FTY720 was evaluated in vitro in hippocampal neuronal cells from neonatal rats and in vivo in rat pups. In vitro cell apoptosis was determined by flow cytometry after exposure to 3 % sevoflurane for different period of time, or after 6-h exposure to sevoflurane with the presence of FTY720, SEW2871 (selective S1P1 receptor agonist) or combination of FTY720 and VPC23019 (S1P antagonist). Western blot analysis was performed with hippocampal tissue from rat pups exposed to 3 % sevoflurane for 6 h with or without pre-treatment with FTY720 injection. Neurological function tests were also performed with rat pups exposed to 3 % sevoflurane for 6 h with or without pre-treatment with FTY720 injection. FTY720, at nanomolar concentration, significantly prevents sevoflurane-induced neuronal apoptosis. SEW2871 showed similar neuroprotective effect to FTY720, whereas VPC23019 abrogated the neuroprotective effect of FTY720 when given together. Western blots results demonstrated that FTY710 significantly preserved the level of phosphorylated ERK1/2, Bcl-2 and Bax. Although anaesthetic treatment did not affect general health and emotional status, sevoflurane-induced cognitive impairment in rat models. Administration of FTY720 at 1 mg/kg significantly attenuated sevoflurane-induced neurocognitive impairment. Although further studies are needed to evaluate the feasibility of clinical usage of FTY720 as neuroprotective agent, the study provides preclinical experimental evidence for the efficacy of FTY720 against sevoflurane-induced developmental neurotoxicity.     

Effects of Naringenin on Oxidative Stress and Histopathological Changes in the Liver of Lead Acetate Administered Rats

Lead has several adverse effects on the body due to one of the environmental pollutants. We aimed to determine the effects of naringenin on the oxidative stress and the hepatic damage against lead acetate treatment in the liver of male rats. Naringenin was administered by orogastric gavage (50 mg/kg) and lead acetate was given as daily 500 parts per million in drinking water for 4 weeks. Lead and antioxidant activities were measured, and histopathological evaluation was performed in the liver. Lead concentrations, malondialdehyde, and antioxidant activity were restored by the naringenin. The grade of necrosis, hydropic degeneration, and hepatic cord disorganization was decreased by the naringenin. However, there were no differences in the degree of sinusoidal congestion, hepatic steatosis, and capsular fibrosis between lead acetate and naringenin + lead acetate groups. We can suggest that naringenin has antioxidant and chelating effects in the liver. Nevertheless, this effect is not enough against the lead acetate induced hepatic injury.     

Towards the Development of a Biologically based Dose-Response Model of Lead Neurotoxicity

Biologically-based dose-response (BBDR) paradigms incorporatemechanistic toxicological data in the derivation of quantitativemodels to estimate risk. Developmental lead (Pb) exposure hasbeen long associated with deficits in intellectual ability.To date, direct estimates of toxicant-induced functional alterationsin brain that may underlie cognition have been lacking, obviatingthe utilization of quantitative modeling for toxicological endpointsof higher brain function. The utility of the long-term potentiation(LTP) model of synaptic plasticity in the context of Pb-inducedcognitive deficits is explored in the present paper. In reviewingphysiological and biochemical requirements of LTP that may overlapwith cellular mechanisms of Pb toxicity, a neurobiological schemais constructed upon which we can begin to explore the possibilityof applying BBDR models in neurotoxicology.     

Flaxseed Oil for Control of Peanut Rust and Its Disease Control Mechanism

Severity of peanut rust caused by Puccinia arachidis was reduced by 15 edible oils tested. Flaxseed oil was the best suppressing the disease completely. Peanut oil, wheat germ oil, brown rice oil, aloe oil, olive oil and corn germ oil also caused more than 75% reduction in disease incidence. Flaxseed oil reduced the rust to a negligible level in the greenhouse and was nearly as effective as the fungicide chlorothalonil in peanut field trials. The control of peanut rust by flaxseed oil did not result from activation of the host defence mechanisms. Flaxseed oil did not affect urediniospore germination, but reduced the germ tube length and completely suppressed appressorium formation which is essential for the pathogen to form an infection peg to pass through the stomatal aperture and infect the host tissue. Although the pathogen had penetrated, flaxseed oil still exerted some inhibitory effect against the growth of the pathogen. The advantages of using flaxseed oil to control peanut rust are that it is relatively inexpensive, easy to prepare, and friendly to the environment and human health.     

Effects of Dietary Fish Oil on Polyunsaturated Fatty Acid Desaturation in Fetal and Postnatal Rats

The effects were determined of dietary fish oil on the polyunsaturated fatty acid desaturation in rats fed on fish oil-containing diets (FS group) and on non-fish oil diets (CN group) during the fetal to postnatal periods. Although the desaturase activity in the liver microsomes of the FS group was higher than that of the CN group before birth, this was not altered by dietary fish oil after birth. However, a lower 20:4n-6 concentration before and after birth, and lower linoleic acid desaturation index ((dihomo-γ-linolenic acid + arachidonic acid)/linoleic acid)) at 10 wk of age in the FS group than in the CN group were observed in the liver microsomal phospholipids. The Δ6-desaturase activity in the brain microsomes of the FS group was lower than that of the CN group. These findings suggest that an intake of dietary fish oil by dams and postnatal rats affected the arachidonic acid concentration due to the decreased desaturase activity in the rats’ microsomes.     

Potential Protective Effect of Coenzyme Q10 on Doxorubicin-Induced Neurotoxicity and Behavioral Disturbances in Rats

Neurochemical Research - The aim of this study was to investigate the potential neuroprotective efficacy of coenzyme Q10 (CoQ10) against doxorubicin (DOX) -induced behavioral disturbances in rats....     

艾芬地尔对异氟烷所致发育期海马神经元毒性的保护作用

目的:通过体外实验探讨艾芬地尔对异氟烷所致发育期海马神经元毒性的保护作用。方法:从出生一天的大鼠海马获取神经元并体外培养5天。这些神经元被随机分入4组,包括对照组(control组)、异氟醚组(Iso组)、艾芬地尔(Ifen组)和艾芬地尔+异氟烷组(Ifen+ISO组)。使用MTT法检测细胞活力及细胞损伤程度。使用TUNEL染色法检测细胞凋亡。使用Western blot法检测神经元中NMDA受体亚基NR2B和活化caspase-3的表达水平。结果:与对照组比较,在2.4%异氟烷暴露后1小时神经元的细胞活力显著下降(P0.05)。同时,在2.4%异氟烷暴露后神经元的凋亡指数也显著升高(P0.05)。Western blot结果显示,异氟烷暴露可显著升高神经元活化caspase-3和NR2B的表达水平(P0.05)。然而,使用NR2B拮抗剂艾芬地尔(20μM)不仅可显著减少异氟烷所致的NR2B表达水平增高,也可缓解异氟烷造成的神经元凋亡和细胞损伤(P0.01)。结论:异氟烷可导致发育期神经元NR2B表达水平增高,而使用NR2B受体拮抗剂艾芬地尔可有效抑制NR2B的表达水平从而减少异氟烷所致神经元毒性。