Nicotinamide attenuates the decrease of astrocytic phosphoprotein PEA-15 in focal cerebral ischemic injury

Nicotinamide exerts neuroprotective effects against focal cerebral ischemic injury. Phosphoprotein enriched in astrocytes 15 (PEA-15) is prominently expressed in astrocytes that exert broad anti-apoptotic functions. This study investigated whether nicotinamide modulates PEA-15 and levels of two phosphorylated PEA-15 (Serine 104 and 116) in an animal model of middle cerebral artery occlusion (MCAO)-induced injury. Adult male rats were treated with vehicle or nicotinamide (500 mg/kg) 2 hr after the onset of MCAO and cerebral cortices were collected at 24 hr after MCAO. In a proteomic approach, MCAO induced decreases of PEA-15 levels, while nicotinamide treatment attenuated the injury-induced decrease in PEA-15. The results of Western blot analysis suggest that nicotinamide prevented injury-induced reduction in phospho-PEA-15 (Serine 104) and phospho-PEA-15 (Serine 116) levels. The phosphorylation of PEA-15 exerts anti-apoptotic functions, and reduction of PEA-15 phosphorylation leads to apoptotic cell death. These results suggest that nicotinamide exerts a neuroprotective effect by attenuating the injury-induced decreases of PEA-15 and phospho-PEA-15 (Ser 104 and Ser 116) proteins.     

Beta-lactam antibiotics prevent Salmonella-mediated bovine encephalopathy regardless of the β-lactam resistance status of the bacteria

This study assessed the capacity of β-lactam antibiotics to prevent salmonella-mediated encephalopathy in calves given the putative neuroprotective effects of these drugs of increasing glutamate export from the brain. Both ampicillin and ceftiofur prevented the development of encephalopathy despite resistance of the inoculated Salmonella enterica serovar Saint-Paul isolate to both drugs. A glutamate receptor antagonist also prevented this salmonella-mediated encephalopathy. Glutamate exporters were hyper-expressed in the presence of β-lactam antibiotics while a glutamate export inhibitor obviated the effects of these antibiotics, demonstrating a neuroprotective effect through glutamate export from the brain. The findings indicate that β-lactam antibiotics remain an important treatment option for this atypical form of bovine salmonellosis.     

Evaluation of glutamate loss from damaged retinal cells of dogs with primary glaucoma

OBJECTIVE: To determine whether retinal damage in dogs with primary glaucoma (PG) is consistent with ischemia-induced glutamate toxicosis. SAMPLE POPULATION: Retinal tissue sections from 25 dogs with PG and 12 normotensive control dogs. PROCEDURE: Retinal sections from control and glaucomatous dogs were stained for morphometric and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) analyses to determine whether retinal damage was consistent with glutamate toxicosis. Immunohistochemical analysis was performed to detect ischemia-like loss of glutamate from neurons in damaged areas. RESULTS: In severely damaged glaucomatous retinas, all neurosensory layers had focal regions that were thin or disrupted. There was less thinning of the outer nuclear layer (ONL) and inner nuclear layer (INL) in moderately damaged retinas than in severely damaged retinas. Acute signs of damage in the INL included cells with dark, condensed chromatin and lightly stained cytoplasm interspersed with a few TUNEL-positive cells, which was consistent with glutamate toxicosis. Glutamate immunoreactivity was reduced in thin areas and in damaged cells of the INL and ONL, which was consistent with glutamate release in damaged areas. Glutamate immunoreactivity was increased in putative Müller cells in damaged areas, which also was consistent with glutamate release. CONCLUSIONS AND CLINICAL RELEVANCE: Retinal damage in dogs with PG differs in intensity in focal areas. Damage in affected regions resembles damage induced by glutamate. Glutamate is lost from damaged neurons and accumulates in Müller cells, which is consistent with increased glutamate release contributing to the damage. Glutamate antagonists may protect INL cells in dogs with glaucoma.     

白藜芦醇对急性热应激条件下鸭肝抗氧化能力和细胞凋亡的影响

旨在探索饲粮中添加白藜芦醇对急性热应激条件下山麻鸭肝抗氧化能力和细胞凋亡的影响,确定添加白藜芦醇对山麻鸭肝组织SIRT1信号通路、抗氧化酶系统及凋亡相关基因的作用。试验选取120只60日龄体重相近且健康的雌性山麻鸭,随机分为2组,每组60只,既对照组(C,饲喂基础饲粮)和白藜芦醇组(RES,饲喂添加400 mg·kg^-1白藜芦醇的基础饲粮)。两组动物均在常温(24℃±2℃)下饲养,15 d后,两组动物体重无明显差异。随后分别将每组动物随机分为3组,每组20只,在39℃环控仓中分别放置0、30、60 min。热应激处理后,采集鸭血清样本及肝组织,应用qRT-PCR、Western blot、TUNEL技术对SIRT1信号通路及凋亡相关基因的mRNA、蛋白水平和细胞凋亡数进行检测。采用生化法检测血清及肝中的氧化指标。结果显示,与对照组相比,白藜芦醇组HSP70和HSP90 mRNA表达有所升高。同时,白藜芦醇激活了SIRT1途径,增加了下游PGC-1α、TFAM mRNA表达,显著增加了热应激60 min条件下Nrf1、Nrf2核蛋白的表达。白藜芦醇提高了血清中T-A...     

The role of glutamate in central nervous system health and disease--a review

Glutamate is the principal excitatory neurotransmitter in the brain. Knowledge of the glutamatergic synapse has advanced enormously over the last 10 years, primarily through application of cellular electrophysiological and molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic glutamate receptors with intrinsic cation permeable channels. There are also three groups of metabotropic, G-protein-coupled glutamate receptors that can modify neuronal excitability. There are also two glial glutamate transporters and three neuronal transporters in the brain. Endogenous glutamate may contribute to the brain damage occurring acutely after traumatic brain injury as well as having a role in the excitatory imbalance present in epileptic conditions and contributing to the pathophysiology of hepatic encephalopathy in animals. Understanding the role of glutamate in these neurological diseases may highlight treatment potentials of antagonists to glutamatergic transmission. This paper presents a review of the literature of glutamate and its role in neurological function and disease.     

The modification of the toxic effects of phenyl mercury by the adaptive reactions of the rat kidney. 1. Timely development of adaptation

Doses of 0.5 mg/kg body weight, 1.5 mg/kg, 3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg of phenylmercury acetate (PMA), as a model substance, were administered to Ico:WIST rats, over periods of 1, 5, 20, and 40 days, for the purpose of studying time-dependent and dose-related buildup of adaptive alterations in kidney. Substance-related damage to kidneys was assessed with reference to functional and morphological parameters. Application of organic PMA resulted exclusively in accumulation in kidneys of inorganic Hg, as had been shown by determination of residues. One single application of a toxic dose of phenylmercury acetate caused severe structural and functional necrobiotic damage. Repetitive applications caused renal damage in response to lower daily doses but caused also adaptation of kidneys to effect of higher doses. Adaptation was characterised by unambiguous reduction in necrosis, increase in regenerative cells in tubular epithelium, limited enzyme excretion in urine as well as restitution of impaired functional parameters and proteinuria. These findings are discussed in some detail, with reference being made to effects of other Hg compounds and possible mechanisms of adaptation.     

Curcumin attenuates the effects of transport stress on serum cortisol concentration, hippocampal NO production, and BDNF expression in the pig

Curcumin, the active component of curcuma longa, has been reported to be effective in alleviating chronic stress-induced disorders in rodents by modulating neuroprotection and neuroendocrine functions of the central nervous system, especially hippocampus. However, it is unclear whether curcumin can attenuate the subacute stress response induced by 2 h of road transport in the pig. Therefore, the present study was designed to identify the changes of serum cortisol concentration, hippocampal nitric oxide (NO) production, and related gene expression in response to 2 h of transport and to explore whether curcumin treatment (8 mg/kg, p.o.) for 21 d before transport may alleviate the stress-induced responses in the hippocampus of pigs. We found that 2 h of transport elevated serum cortisol concentration (P < 0.01), increased hippocampal NO content, and reduced brain-derived neurotrophic factor (BDNF) mRNA expression in pigs not treated with curcumin, whereas these stress responses were all reversed or attenuated in curcumin-treated pigs. In addition, the stress-induced increase in the expression of constitutive nitric oxide synthase (cNOS) and enzyme activities of total NOS, cNOS, and inducible NOS (iNOS) was also reversed or attenuated in curcumin-treated pigs. However, neither transport nor curcumin caused significant alterations in hippocampal expression of 11β-hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 2), glucocorticoid and mineralocorticoid receptors (GR and MR), or pro-/anti-apoptotic molecules (Bax-α and Bcl-xL). These results suggest that curcumin can alleviate subacute stress response in pigs through its neuroprotective effects on modulating hippocampal NO production and BDNF expression.     

Excitotoxicity can be mediated through an interaction within the optic nerve; activation of cell body NMDA receptors is not required

Axonal trauma leads to a series of pathologic events that can culminate in neuronal death. Although the precise mechanisms of retinal ganglion cell death after optic nerve crush in the rat model have not been elucidated, glutamate antagonists can protect retinal ganglion cells after optic nerve axotomy. We therefore explored whether a glutamate congener was toxic if applied directly within the optic nerve, or if toxicity depended upon an interaction at the cell body level. NMDA reduced retinal ganglion cell survival when applied directly into the rat optic nerve. Glutamate can be toxic if administered within the optic nerve; a direct effect at the cell body is not necessary. Future work will help to additionally unravel the steps by which axotomy induces excitotoxic damage to ganglion cells, and perhaps indicate protective interventions.     

Melatonin regulates nitric oxide synthase expression in ischemic brain injury

Nitric oxide (NO) is produced by three NO synthases (NOS), iNOS, eNOS, and nNOS. Production of NO by iNOS plays key roles in neurodegeneration, while eNOS is a protective enzyme. This study investigated the neuroprotective effect of melatonin and the levels of NOS isoforms induced by melatonin in ischemic brain injury. Adult male rats were treated with melatonin (5 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO). Brain samples were collected at 24 hr after the onset of occlusion. Results confirmed that melatonin significantly reduces infarct area. Western blot analysis was used to evaluate the expression levels of iNOS, eNOS, and nNOS. The level of iNOS and nNOS increased in vehicle-treated animals, while melatonin prevented injury-induced increase of iNOS. In contrast to iNOS levels, eNOS levels decreased in vehicle-treated animals, while melatonin prevented the injury-induced decrease of eNOS. This study provides further evidence that melatonin exerts neuroprotective effects, and the regulation of NOS isoforms by melatonin may contribute to the neuroprotective effects.     

Comparative studies on the distribution of glutamate transporters in the retinae of the Mongolian gerbil and the rat

Glutamate is the major excitatory amino acid transmitter in vertebrate retinae. Glutamate transporters therefore play an important role in the precise control of glutamate concentration in the synaptic cleft by regulating extracellular glutamate concentration. In the present study, we performed an analysis of the expressions of three glutamate transporters in gerbil retina using immunohistochemistry. In the gerbil retina, excitatory amino acid carrier 1 and glutamate transporter 1 immunoreactivity was predominant in the ganglion cells but not amacrine or bipolar cells. Glutamate/aspartate transporter (GLAST) immunoreactivity was observed in the radial gliocytes of which the dense network of fine processes was localized in the inner and outer plexiform layers. GLAST immunoreactivity was also detected in astrocytes in the nerve fibre layer. These results demonstrate that three glutamate transporters show specific distributions in the gerbil retina and suggest that the glutamate re-uptake system in the gerbil retina may be different from that of the rat.     

Contrasting effects of nitrofurans on plasma corticosterone in chickens following administration as a bolus or diet additive

Administration of furazolidone as a bolus dose (8-500 mg/kg), produced a decrease in plasma corticosterone in chickens. In contrast, addition of furazolidone or furaltadone to the diet (0.04% or above, 10 days), increased plasma corticosterone. Pre-treatment with a 200-mg/kg bolus of furazolidone or furaltadone did not affect pentobarbitone anaesthesia time in the birds. In chickens pre-treated with a nitrofuran in the diet, however, pentobarbitone anaesthesia time was significantly less than that in controls. Furaltadone in the diet, produced significant increases in the amount of cytochrome P-450 and the activity of aniline hydroxylase in the liver microsomes. It is suggested that nitrofurans given in the diet stimulated corticosterone biosynthesis in the adrenal glands and induced mixed-function oxidase activity in the liver. Nitrofurans given as a bolus did not produce these effects. Furazolidone (200 mg/kg) produced severe anorexia, which lasted 2 days in T-line birds. The anorexia seemed to be associated with tissue damage in the birds rather than the ensuing adrenal cortical insufficiency.     

Effect of resveratrol on growth performance,rectal temperature and serum parameters of yellow‐feather broilers under heat stress

This study investigated the effect of dietary resveratrol supplementation on growth performance, rectal temperature, and serum parameters of yellow‐feather broilers under heat stress. A total of 480 yellow‐feather broilers (28‐day‐old) were randomly allotted to five groups with six replicates. A thermoneutral group (TN) (24 ± 2°C) received a basal diet and another four heat‐stressed groups (37 ± 2°C for 8 hr/day and 24 ± 2°C for the remaining time) were fed the basal diet or basal diet with 200, 350, and 500 mg/kg resveratrol for 14 consecutive days. The results revealed that resveratrol supplementation improved average daily gain (p = 0.001), and decreased (p < 0.05) rectal temperature from d 3 when compared with heat‐stressed group without resveratrol. In addition, supplementation with resveratrol at 350 or 500 mg/kg lowered (p < 0.05) the contents of corticosterone, adrenocorticotropic hormone, cholesterol, triglycerides, uric acid, malonaldehyde, and activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, increased (p < 0.05) the levels of triiodothyronine, the ratio of triiodothyronine to thyroxine, total protein, glutathione, and activities of alkaline phosphatase, total superoxide dismutase, catalase, and glutathione peroxidase, though with few fluctuation. In conclusion, supplementation with resveratrol can improve the growth performance by positively regulating serum metabolic parameters and alleviating tissue oxidant damage of broilers under heat stress.     

Streptozocin-induced pancreatic islet destruction in beef cows.

Streptozocin (STZ) induces diabetes mellitus in sheep and pigs. To test the effect of STZ in cattle, cows were given 75-150 mg STZ per kilogram of body weight. Cows receiving 150 mg/kg required euthanasia within 24 hours after infusion because of the severe systemic effects of STZ. Seven cows receiving doses of < or = 100 mg/kg had mild to marked decrease in islet immunoreactivity for insulin and in pancreatic islet density and mild to severe tubulointerstitial nephritis. Two cows receiving 75 and 85 mg/kg STZ regained their ability to produce insulin and return blood glucose to basal levels. One cow given 100 mg/kg STZ developed insulin insufficiency consistent with type I diabetes mellitus. These findings demonstrate the susceptibility of the bovine pancreas to STZ: however, severe systemic complications were encountered. Alternative dosages and methodologies should be considered in future attempts to induce diabetes in cattle using STZ.     

Content of ileal EAAC1 and hepatic GLT-1 high-affinity glutamate transporters is increased in growing vs. nongrowing lambs,paralleling increased tissue D- and L-glutamate,plasma glutamine,and alanine concentrations

Glutamate is a central metabolite for whole-animal energy and N metabolism. This study tested the hypothesis that ileal epithelium, liver, and kidney content of system X-(AG) glutamate transporters EAAC1 and GLT-1 would be up-regulated to support growth of wethers (30 +/- 1.2 kg) fed a forage-based diet for at least 14 d to gain (2.0 x NEm; n = 9) vs. maintain (1.2 x NEm; n = 9) BW. We have previously demonstrated that two high-affinity glutamate transporters (EAAC1, GLT-1) are expressed by these extensive glutamate metabolizing epithelial tissues. Wethers fed at 2.0 x NEm gained (P < 0.001; 0.26 kg/d) BW, whereas those fed 1.2 x NEm did not. Although plasma concentrations (microM) of glucose and L- or D-glutamate did not differ, plasma glutamine (precursor of glutamate) and alanine concentrations (transamination product of glutamate) were 28% (P < 0.007) and 22% (P < 0.072) greater for growing lambs than nongrowing lambs. In tissues, the concentration of L-glutamate in ileum epithelia and D-glutamate of liver was 49% (P < 0.015) and 181% (P < 0.042) greater, respectively, in growing vs. nongrowing animals, whereas concentrations of glutamate isoforms did not differ in kidney. Paralleling these increased amino acid concentrations, ileal epithelium contained 313% more (P < 0.038) EAAC1 protein and liver contained 240% more (P < 0.001) GLT-1 protein, whereas kidney transporter content did not differ between growing and nongrowing wethers. In contrast to increased EAAC1 and GLT-1 protein content in ileal and liver tissue of growing lambs, messenger RNA levels did not differ. These results indicate that the increased capacity for high-affinity glutamate uptake in growing vs. nongrowing lambs is achieved through increased expression of EAAC1 by ileal epithelium and GLT1 by liver, which parallel increased tissue concentrations of glutamate and plasma concentrations of two major interorgan N carriers, glutamine and alanine.     

Changing of antioxidant enzyme activity on the biliary obstructed rats treated with resveratrol

The aim of this study was to evaluate the role of antioxidant enzyme activity and nitric oxide levels induced by 28 day biliary obstruction in the rat. A total of 21 young Swiss albino rats were divided in to 3 groups. Bile duct ligations, bile duct ligations plus resveratrol, sham operated. Bile duct ligations plus resveratrol group received 10 mg/kg dose of resveratrol intraperitonealy once daily throughout for 28 days. Liver damage and cholestasis were determined by biochemical examination. SOD, CAT and GSH-PX activity decreased in BDL group compared with shame opareted groups (p < 0.001). NO levels increased in BDL groups compared with shame opareted groups (p < 0.001). SOD, CAT and GSH-PX activity was found higher in BDL+resveratrol treated groups than BDL groups (p < 0.001). In addition this NO levels decreased in BDL+resveratrol treated groups than BDL groups (p < 0.001). In conclusion, it is thought that resveratrol may be used as a protective agent in biliary obstructions; however, further clinical and experimental studies are needed to verify its antioxidative and hepatoprotective effects.     

N,N'-Bis(2-chloroethyl)-N-nitrosourea (BCNU)-induced Apoptosis of Neural Progenitor Cells in the Developing Fetal Rat Brain

N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) is one of the major drugs used in chemotherapy against malignant gliomas due to its effects, such as induction of bifunctional alkylation of DNA and formation of interstrand DNA cross-linkages, and induces cortical malformations in the fetal and neonatal rat brain. In this study, pregnant rats were treated with 7.5 mg/kg of BCNU on gestational day 13 (GD 13), and their fetuses were collected from 12 to 72 hours after BCNU treatment in order to examine the timecourses of morphological and immunohistochemical changes in neural progenitor cells in the developing brain. The number of pyknotic cells in the telencephalon peaked at 24 h and then gradually decreased until 72 h. The majority of these pyknotic cells were positive for cleaved caspase-3, a key executioner of apoptosis. The pyknotic cells showed the ultrastructural characteristics of apoptosis. The number of p53-positive cells began to increase prior to the appearance of apoptotic cells and p21-positive cells. The number of phosphorylated-histone H3-positive cells (mitotic cells) decreased from 24 to 36 h. The number of Iba1-positive cells (microglial cells) in the telencephalon increased from 12 to 48 h. These results suggest that BCNU induces p53-dependent apoptosis and reduces proliferative activity, resulting in reduction of the weight of the telencephalon and the thickness of the telencephalic wall in the fetal brain. This study will help to clarify the mechanisms of BCNU-induced fetal brain toxicity.     

高铜对雏鸡脑组织氧化状态的影响

1日龄艾维茵肉鸡健雏360羽,随机均分为6组,分别喂以对照日粮(10.89 mg/kg)和高铜日粮(Cu 100 mg/kg,高铜Ⅰ组;Cu 200 mg/kg,高铜Ⅱ组;Cu 400 mg/kg,高铜Ⅲ组;Cu 600 mg/kg,高铜Ⅳ组;Cu 800 mg/kg,高铜Ⅴ组)6周,观察高铜对脑组织氧化状态的影响.高铜Ⅱ、Ⅲ、Ⅳ和Ⅴ组脑组织MDA含量升高,与对照组比较差异显著或极显著(P<0.05或P<0.01);脑组织铜-锌-超氧化物歧化酶(Cu-Zn-SOD)和谷胱甘肽过氧化物酶(GSH-Px)的活性,高铜Ⅰ、Ⅱ组显著或极显著高于对照组(P<0.05或P<0.01),高铜Ⅲ、Ⅳ和Ⅴ组较对照组极显著降低(P<0.01);高铜Ⅱ、Ⅲ、Ⅳ和Ⅴ组脑组织羟自由基活性升高,与对照组比较差异显著或极显著(P<0.05或P<0.01).同时,血清的MDA含量及Cu-Zn-SOD和GSH-Px的活性变化与脑组织一致.结果表明,日粮铜水平在400 mg/kg及以上时,脑组织的抗氧化功能受损.