Changes in Histamine Metabolism in the Mouse Hypothalamus Induced by Acute Administration of Ethanol

The effect of acute ethanol administration on histamine (HA) dynamics was examined in the mouse hypothalamus. The steady-state level of HA did not change after intraperitoneal administration of ethanol (0.5-5 g/kg), whereas the level of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, increased when 3 and 5 g/kg of ethanol was given. Pargyline hydrochloride (80 mg/kg, i.p.) increased the level of t-MH by 72.2% 90 min after the treatment. Ethanol at any dose given did not significantly affect the t-MH level in the pargyline-pretreated mice. Decrease in the t-MH level induced by metoprine (10 mg/kg, i.p.), an inhibitor of HA-N-methyltransferase, was suppressed by ethanol (5 g/kg), thereby suggesting inhibition of the elimination of brain t-MH. Ethanol (5 g/kg) significantly delayed the depletion of HA induced by (S)-alpha-fluoromethylhistidine (50 mg/kg, i.v.), a specific inhibitor of histidine decarboxylase. Therefore, a large dose of ethanol apparently decreases HA turnover in the mouse hypothalamus.     

Deficiency of Tenascin-C Alleviates Neuronal Apoptosis and Neuroinflammation After Experimental Subarachnoid Hemorrhage in Mice

Tenascin-C (TNC), a matricellular protein, is upregulated in brain parenchyma after experimental subarachnoid hemorrhage (SAH). Recent studies emphasize that early brain injury (EBI) should be overcome to improve post-SAH outcomes. The aim of this study was to investigate effects of TNC knockout (TNKO) on neuronal apoptosis and neuroinflammation, both of which are important constituents of EBI after SAH. C57BL/6 wild-type (WT) mice or TNKO mice underwent sham or filament perforation SAH modeling. Twenty-five WT mice and 25 TNKO mice were randomly divided into sham+WT (n?=?10), sham+TNKO (n?=?8), SAH+WT (n?=?15), and SAH+TNKO (n?=?17) groups. Beam balance test, neurological score, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, immunostaining of Toll-like receptor 4 (TLR4), and Western blotting were performed to evaluate neurobehavioral impairments, neuronal apoptosis, and neuroinflammation at 24 h post-SAH. Deficiency of TNC significantly alleviated post-SAH neurobehavioral impairments and neuronal apoptosis. The protective effects of TNKO on neurons were associated with the inhibition of a caspase-dependent apoptotic pathway, which was at least partly mediated by TLR4/nuclear factor-κB/interleukin-1β and interleukin-6 signaling cascades. This study first provided the direct evidence that TNC causes post-SAH neuronal apoptosis and neuroinflammation, potentially leading to the development of a new molecular targeted therapy against EBI.     

Modafinil Abrogates Methamphetamine-Induced Neuroinflammation and Apoptotic Effects in the Mouse Striatum

Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4×5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2×90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.     

Increased Light Exposure Alleviates One Form of Photoreceptor Degeneration Marked by Elevated Calcium in the Dark

Background

In one group of gene mutations that cause photoreceptor degeneration in human patients, guanylyl cyclase is overactive in the dark. The ensuing excess opening of cGMP-gated cation channels causes intracellular calcium to rise to toxic levels. The Y99C mutation in guanylate cyclase-activating protein 1 (GCAP1) has been shown to act this way. We determined whether prolonged light exposure, which lowers cGMP levels through activation of phototransduction, might protect photoreceptors in a line of transgenic mice carrying the GCAP1-Y99C.

Methodology/Principal Findings

We reared cohorts of GCAP1-Y99C transgenic mice under standard cyclic, constant dark and constant light conditions. Mouse eyes were analyzed by histology and by immunofluorescence for GFAP upregulation, a non-specific marker for photoreceptor degeneration. Full-field electroretinograms (ERGs) were recorded to assess retinal function. Consistent with our hypothesis, constant darkness accelerated disease, while continuous lighting arrested photoreceptor degeneration.

Conclusions/Significance

In contrast to most forms of retinal degeneration, which are exacerbated by increased exposure to ambient light, a subset with mutations that cause overly active guanylyl cyclase and high intracellular calcium benefitted from prolonged light exposure. These findings may have therapeutic implications for patients with these types of genetic defects.     

Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission

Neuroinflammation and imbalance of neurotransmitters play pivotal roles in seizures and epileptogenesis. Aucubin (AU) is an iridoid glycoside derived from Eucommia ulmoides that possesses anti-inflammatory and neuroprotective effects. However, the anti-seizure effects of AU have not been reported so far. The present study was designed to investigate the effects of AU on pilocarpine (PILO) induced seizures and its role in the regulation of neuroinflammation and neurotransmission. We found that AU reduced seizure intensity and prolonged the latency of seizures. AU significantly attenuated the activation of astrocytes and microglia and reduced the levels of interleukine-1 beta (IL-1β), high mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α). Furthermore, the contents of γ-aminobutyric acid (GABA) were increased while the levels of glutamate were decreased in the hippocampus with AU treatment. The expression of γ-aminobutyric acid type A receptor subunit α1 (GABA_ARα1) and glutamate transporter-1 (GLT-1) protein were up-regulated in AU treatment group. However, AU had no significant effect on N-methyl-d-aspartate receptor subunit 2B (NR2B) expression in status epilepticus (SE). In conclusion, our findings provide the first evidence that AU can exert anti-seizure effects by attenuating gliosis and regulating neurotransmission. The results suggest that AU may be developed as a drug candidate for the treatment of epilepsy.

     

Caveolin-1和黏附分子在LPS诱导的急性肺损伤模型中的变化

通过实时荧光定量PCR(real-time PCR)等方法,研究了脂多糖(lipopolysaccharide,LPS)诱导的急性肺损伤(acute lung injury,ALI)小鼠模型肺组织中小窝蛋白-1(caveolin-1)、血管细胞粘附分子-1(vascular cell adhesion molecule-1,VCAM-1)和E-选择素(E-selectin)的m RNA表达变化情况,以初步探索caveolin-1在ALI发病机制中的作用。实验结果表明,与对照组相比较,经腹腔注射LPS(20 mg/kg)的实验组中肺系数、髓过氧化物酶(myeloperoxidase,MPO)m RNA水平明显升高(P0.05),同时VCAM-1和E-selectin的m RNA表达水平增加(P0.05),而caveolin-1的m RNA表达减少(P0.05)。上述研究提示,LPS可能通过抑制caveolin-1的表达,使黏附分子VCAM-1、E-selectin的表达上调,从而使肺组织中性粒细胞大量浸润,MPO增多,加重肺损伤。     

苯肼致小鼠溶血性贫血模型的建立

目的:应用苯肼致小鼠发生溶血性贫血,建立急性溶血性贫血模型,筛选苯肼致小鼠贫血最佳浓度和红细胞移植的最佳时机。方法:30只C57BL/6小鼠随机分为6组,经腹腔注射不同浓度的苯肼溶液,于注射前和注射后第1、3、5、7、9天采集小鼠外周血进行检测,记录相关指标的变化,比较各组之间的差异,筛选出最佳溶血效果的给药浓度和红细胞移植治疗介入的时机。结果:注射苯肼溶液可使C57BL/6小鼠短期内产生明显的急性溶血性贫血症状,皮肤黏膜颜色苍白;外周血红细胞数量、血红蛋白含量、红细胞压积降低;随着苯肼溶液浓度的增加,小鼠体重显著减轻,存活率下降。结果表明,苯肼注射小鼠致贫血的最佳作用浓度为1.2mg/10g体重,小鼠贫血状态可维持7d。结论:建立了小鼠溶血性贫血模型,此模型可应用于红细胞输注效果的评价。     

Role of CD14 in a Mouse Model of Acute Lung Inflammation Induced by Different Lipopolysaccharide Chemotypes

Background

Recognition of lipopolysaccharide (LPS) is required for effective defense against invading gram-negative bacteria. Recently, in vitro studies revealed that CD14 is required for activation of the myeloid differentiation factor (MyD)88-dependent Toll-like receptor (TLR)4 signaling pathway by smooth (S)-LPS, but not by rough (R)-LPS. The present study investigated the role of CD14 in induction of lung inflammation in mice by these different LPS chemotypes.

Methodology/Results

Neutrophil accumulation and tumor necrosis factor (TNF) release in bronchoalveolar lavage fluid were determined 6 hours after intranasal treatment of wild type (WT) and CD14 knock-out (KO) mice with different doses S-LPS or R-LPS. The contribution of CD14 to lung inflammation induced by S-LPS or R-LPS depended on the LPS dose. At low doses, S-LPS and R-LPS induced neutrophil influx in a CD14-dependent manner. Low dose S-LPS-induced cytokine release also depended on CD14. Strikingly, neutrophil influx and TNF release induced by high dose S-LPS or R-LPS was diminished in the presence of CD14. Intranasal administration of sCD14 to CD14 KO mice treated with S-LPS partially reversed the inflammatory response to the response observed in WT mice.

Conclusions

In conclusion, CD14 modulates effects of both S-LPS and R-LPS within the lung in a similar way. Except for R-LPS-induced TNF release, S-LPS and R-LPS at low dose induced acute lung inflammation in a CD14-dependent manner, while the inflammatory response triggered by high dose S-LPS or R-LPS was diminished by CD14.     

Poly-arginine Peptide R18D Reduces Neuroinflammation and Functional Deficits Following Traumatic Brain Injury in the Long-Evans Rat

We have previously demonstrated that the poly-arginine peptide R18 can improve histological and functional outcomes following traumatic brain injury (TBI) in the Sprague–Dawley rat. Since D-enantiomer peptides are often exploited in pharmacology for their increased stability and potency, the present study compared the effects of R18 and its D-enantiomer, R18D, following TBI in the Long-Evans rat. Following a closed-head impact delivered via a weight-drop apparatus, peptide was administered at a dose of 1000 nmol/kg at 30 min after TBI. Treatment with R18D, but not R18 resulted in significant reductions in sensorimotor (p?=?0.026) and vestibulomotor (p?=?0.049) deficits as measured by the adhesive tape removal and rotarod tests. Furthermore, treatment with R18 and R18D resulted in a significant reduction in brain protein levels of the astrocytic marker, glial fibrillary acidic protein (p?=?0.019 and 0.048, respectively). These results further highlight the beneficial effects of poly-arginine peptides in TBI, however additional studies are required to confirm these positive effects.

     

Effects of Melatonin on Memory and Learning Deficits Induced by Exposure to Thinner

The neurotoxic effects of thinner, a mixture including aromatic compounds (in particular, toluene) and widely used as an industrial solvent, were examined. Exposure of rats to high inhalation concentrations (3000 p.p.m.) of thinner for 45 days (1 h per day) significantly influenced the cognitive functions and levels of neural cell adhesion molecules (NCAM) in the hippocampus, cortex, and cerebellum of experimental animals. These exposures also caused dramatic increases in levels of LPO (malondialdehyde and 4-hydroxyalkenals) in these cerebral structures, while melatonin administration significantly reduced the LPO amounts in these brain regions. The level of NCAM (180 kDa) decreased significantly in the hippocampus and cortex of thinner-exposed rats. Furthermore, thinner-exposed rats showed cognitive deficits in the passive avoidance and Morris water maze tasks; these negative effects were considerably compensated in rats additionally chronically treated with melatonin. It is concluded that treatment with melatonin prevents the development of learning and memory deficits caused by thinner exposure, possibly by reducing oxidative stress and normalizing the neural plasticity.     

黄磷及其化合物急性吸入致大鼠急性肺损伤或急性呼吸窘迫综合征模型的制作

目的建立黄磷及其化合物急性吸入致大鼠急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）的模型。方法健康SD大鼠48只随机分为对照组以及实验组（0、4、12、24、48 h时间点处死）。采用自制染毒装置,间歇染毒形成ALI/ARDS模型。观察ALI/ARDS大鼠动脉血气分析以及肺系数和肺组织病理变化。结果肺损伤后大鼠动脉血气分析以及肺组织病理改变明显恶化,肺系数较对照组明显增大。结论成功地建立了黄磷及其化合物急性吸入致大鼠ALI/ARDS的模型,为黄磷及其化合物吸入中毒的防治研究提供良好实验基础,同时也适用于其他气体吸入致ARDS的实验研究。     

Measurement of Free Radicals from Smoke Inhalation and Oxygen Exposure by Spin Trapping and Esr Spectroscopy

Research in smoke inhalation has established that free radicals are produced from gases released during combustion and these species impair lung function. Using spin traps and their adducts in an animal model free radicals were measured. Various hyperbaric oxygen regimens were tested in an attempt to attenuate pulmonary damage caused by free radical reactions. Our data demonstrated that persistent oxygen- and carbon-centered free radicals are detectable in intravascular fluids after smoke inhalation. The smoke inhalation model showed however, clearing of spin trap adducts one hour after smoke exposure. Other researchers have found that when 100% oxygen is given at 1 atmosphere absolute (ATA) for 1 h, free radicals were not detectable. However, oxygen given at 2.5 ATA does produce detectable free radicals. With continued exposure at this pressure, the levels of free radicals increase for up to 60min. This study suggests that the level of free radical induced oxygen toxicity may be a function of oxygen pressure and duration of oxygen exposure.     

Acute Treatment with Bis Selenide, an Organic Compound Containing the Trace Element Selenium, Prevents Memory Deficits Induced by Reserpine in Rats

Taking into account the promising pharmacological actions of (Z)-2,3-bis(4-chlorophenylselanyl) prop-2-en-1-ol) (bis selenide), an organic compound containing the trace element selenium, and the constant search for drugs that improve the cognitive performance, the objective of the present study was to investigate whether bis selenide treatment ameliorates memory deficits induced by reserpine in rats. For this aim, male adult rats received a single subcutaneous injection of reserpine (1 mg/kg), a biogenic amine-depleting agent used to induce memory deficit. After 24 h, bis selenide at doses of 25 and 50 mg/kg was administered to rats by intragastric route, and 1 h later, the animals were submitted to behavior tasks. The effects of acute administration of bis selenide on memory were evaluated by social recognition, step-down passive avoidance, and object recognition paradigms. Exploratory and locomotor activities of rats were determined using the open-field test. Analysis of data revealed that the social memory disruption caused by reserpine was reversed by bis selenide at both doses. In addition, bis selenide, at the highest dose, prevented the memory deficit resulting from reserpine administration to rats in step-down passive avoidance and object recognition tasks. No significant alterations in locomotor and exploratory behaviors were found in animals treated with reserpine and/or bis selenide. Results obtained from distinct memory behavioral paradigms revealed that an acute treatment with bis selenide attenuated memory deficits induced by reserpine in rats.     

Learning and Memory Deficits in APP Transgenic Mouse Models of Amyloid Deposition

Several different transgenic APP mice develop learning and memory deficits. In some cases the mice have deficits very early in life, while in other instances the mice exhibit deficits only after they have aged and amyloid deposits have accumulated. In many cases, there is a correlation in individual mice of the same age and genotype between the extent of learning and memory deficits and the amounts of deposited amyloid found in the central nervous system. While superficially this might imply that the deposited material is somehow toxic to cognition, it is likely that deposited amyloid is also an index of the overall rate of amyloid production in each mouse. Rate of production would be expected to modify not only the amounts of deposited amyloid, but also other amyloid pools, including soluble, oligomeric, conjugated (e.g. ADDLs) and intracellular. Thus, the deposited material may be an integrated reflection of total Aß production, in addition to indicating the amounts in fibrillar forms. As such, it is conceivable that other Aß pools may be more directly linked to memory deficits. Thus far, the one manipulation found to mitigate the learning and memory deficits in APP transgenic mice is immunotherapy for Aß, either using active or passive immunization against the peptide. These data together with other findings are leading to a conclusion that the fibrillar Aß deposits are not directly linked to the memory deficits in mice, and that some other Aß pool, more readily diminished by immunotherapy, is more directly linked to the mechanisms leading to poor performance in learning and memory tasks.     

Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats

Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.     

The Oxidative Stress May be Induced by the Elevated Homocysteine in Schizophrenic Patients

The mechanisms of oxidative stress in schizophrenic patients are not fully understood. In the present study, we investigated the effect of elevated level of homocysteine (Hcys) on some parameters of oxidative stress, namely thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation in plasma, the level of carbonyl groups in plasma proteins, as well as the amount of 3-nitrotyrosine in plasma proteins isolated from schizophrenic patients. Patients hospitalised in I and II Psychiatric Department of Medical University in Lodz, Poland were interviewed with special questionnaire (treatment, course of diseases, dyskinesis and other EPS). According to DSM-IV criteria all patients had diagnosis of paranoid type. They were treated with antipsychotic drugs (clozapine, risperidone, olanzapine). Mean time of schizophrenia duration was about 5 years. High-performance liquid chromatography was used to analyse the total level of homocysteine in plasma. Levels of carbonyl groups and 3-nitrotyrosine residues in plasma proteins were measured by ELISA and a competition ELISA, respectively. The lipid peroxidation in plasma was measured by the level of TBARS. Our results showed that in schizophrenic patients the amount of homocysteine in plasma was higher in comparison with the control group. We also observed a statistically increased level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine in plasma proteins from schizophrenic patients. Moreover, our experiments indicate that the correlation between the increased amount of homocysteine and the oxidative stress exists. Considering the data presented in this study, we suggest that the elevated Hcys in schizophrenic patients may stimulate the oxidative stress.     

Bacopaside-I Alleviates the Detrimental Effects of Acute Paraquat Intoxication in the Adult Zebrafish Brain

Neurochemical Research - Paraquat (PQ), an environmental neurotoxicant, causes acute fatal poisoning upon accidental or intentional ingestion (suicidal cases) worldwide. To date, an effective...     

Changes in the Level of DNA Damage in Mouse Cells Induced by Atmospheric Factors

Biophysics - Abstract—Changes in the level of DNA damage induced by atmospheric factors were evaluated from the percentage of tail DNA (%TDNA) in the comet assay of mouse cells for blood...     

A Comprehensive Study on the Mechanistic Way of Hexaflumuron and Hymexazol Induced Neurobehavioral Toxicity in Rats

Neurochemical Research - Pesticides are widely used in agriculture to kill pests, but their action is non-selective and results in several hazardous effects on humans and animals. Pesticide...