Acute Immobilization Research Articles

The influence of oligopeptides - the homologues of ACTH15-18 on the liver and adrenal glands in the rats on the model of acute immobilization stress

An in-depth study the possible links of the stress-protective action of oligopeptides - homologues of the of adrenocorticotropic hormone fragment (15-18) on the model of acute immobilization stress has been carried out. A marked antioxidant effect, not inferior to the reference medicine “Semax”, has been detected in the blood serum and liver of the rats. The results of the morphological study of liver tissue also indicate the normalization of the stress-induced damage in the organ under the influence of oligopeptides (KK-1, KK-5). Both peptides have been exceeded the reference drug, however, the peptide KK-1 had the marked positive effect on the reduction of histological structure of the liver. The stress-protective action of the investigated oligopeptides KK-1 and KK-5 is confirmed by their ability to reduce the increased activity of steroidogenesis and reduce the release of catecholamines, as well as normalize the damaged structure of the adrenal cortex. According to the indices of the adrenal structure recovering, the peptide KK-1 exceeded the reference drug and the peptide KK-1. (For citation: Kudina OV, Shtrygol’ SYu, Kolobov AA, Larjanovskaja YuB, et al. The influence of oligopeptides - the homologues of ACTH15-18 on the liver and adrenal glands in the rats on the model of acute immobilization stress. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(4):30-37. doi: 10.17816/RCF15430-37).

Cadmium-induced biomarkers discovery and comparative network analysis in Daphnia magna

Exposure to cadmium is gradually increased and its toxicity can be fatal to organisms in aquatic environment. D. magna inhabits in water. It is recommended by OECD guideline to test toxicity of chemicals. Through acute immobilization test, we observed a mobility change of D. magna caused by cadmium chloride exposure. The EC50 value of cadmium chloride was 14.5 ppb. Using D. magna in EC50 value of cadmium, we conducted microarray analysis to investigate differential gene expression and found 247 up- and 146 down-regulated genes. We performed BLAST analysis to identify and understand the meaning of the microarray data in comparative genomics. Comparing common proteins in some species, potential biomarkers and functions are discovered through pathway analysis. Based on differential gene expression of cadmium-treated D. magna, potential biomarkers are identified and investigated by functional network of mammals including human through comparative genomic analysis.

Altered Ethanol Consumption in Osteocalcin Null Mutant Mice.

Osteocalcin (OC) is an abundant extracellular calcium-binding protein synthesized by osteoblasts. Although most OC is bound to hydroxyapatite mineral during bone formation, a consistent amount is released directly to circulation. Plasma OC (pOC) levels are highly sensitive to stressful stimuli that alter stress-responsive hormones, such as glucocorticoids (cortisol or corticosterone) and the catecholamines norepinephrine and epinephrine. To gain a better understanding of the apparent relationship of OC to the effects of ethanol (EtOH) and the stress responses, we compared mice that have OC (WT [OC+/+] and HET [OC+/-]) with OC null mutants (KO [OC-/-]), which have no OC in either plasma or in bone. One experiment included chronic unpredictable stress, a second was conducted in the absence of any known stressors other than EtOH, while a third imposed a more severe acute immobilization stress in addition to EtOH consumption. The data obtained confirmed significant differences in EtOH consumption in mice that previously experienced various stressful stimuli. We also determined that adrenal tyrosine-hydroxylase expression was inversely proportional to EtOH consumption and tended to be lower in KO than in WT. Data suggest that OC possesses the ability to modulate the adrenal gene expression of the catecholamine synthetic pathway. This modulation may be responsible for differences in EtOH consumption under stress.

Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses

Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1β in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1β and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.

Toxicity of emerging antifouling biocides to non-target freshwater organisms from three trophic levels

Antifouling (AF) systems provide the most cost-effective protection against biofouling. Several AF biocides have, however, caused deleterious effects in the environment. Subsequently, new compounds have emerged that claim to be more environment-friendly, but studies on their toxicity and environmental risk are necessary in order to ensure safety. This work aimed to assess the toxicity of three emerging AF biocides, tralopyril, triphenylborane pyridine (TPBP) and capsaicin, towards non-target freshwater organisms representing three trophic levels: algae (Chlamydomonas reinhardtii), crustacean (Daphnia magna) and fish (Danio rerio). From the three tested biocides, tralopyril had the strongest inhibitory effect on C. reinhardtii growth, effective quantum yield and adenosine triphosphate (ATP) content. TPBP caused sub-lethal effects at high concentrations (100 and 250μgL−1), and capsaicin had no significant effects on algae. In the D. magna acute immobilisation test, the most toxic compound was TPBP. However, tralopyril has a short half-life and quickly degrades in water. With exposure solution renewals, tralopyril's toxicity was similar to TPBP. Capsaicin did not cause any effects on daphnids. In the zebrafish embryo toxicity test (zFET) the most toxic compound was tralopyril with a 120h − LC50 of 5μgL−1. TPBP’s 120h − LC50 was 447.5μgL−1. Capsaicin did not cause mortality in zebrafish up to 1mgL−1. Sub-lethal effects on the proteome of zebrafish embryos were analysed for tralopyril and TPBP. Both general stress-related and compound-specific protein changes were observed. Five proteins involved in energy metabolism, eye structure and cell differentiation were commonly regulated by both compounds. Tralopyril specifically induced the upregulation of 6 proteins implicated in energy metabolism, cytoskeleton, cell division and mRNA splicing whilst TPBP lead to the upregulation of 3 proteins involved in cytoskeleton, cell growth and protein folding. An ecological risk characterization was performed for a hypothetical freshwater marina. This analysis identified capsaicin as an environment-friendly compound while tralopyril and TPBP seem to pose a risk to freshwater ecosystems. Noneless, more studies on the characterization of the toxicity, behaviour and fate of these AF biocides in the environment are necessary since this information directly affects the outcome of the risk assessment.

Interaction patterns and toxicities of binary and ternary pesticide mixtures to Daphnia magna estimated by an accelerated failure time model

Organisms in natural environments are often exposed to a broad variety of chemicals, and the multi-chemical mixtures exposure may produce significant toxic effects, even though the individual chemicals are present at concentrations below their no-observed-effect concentrations. This study represents the first attempt that uses the accelerated failure time (AFT) model to quantify the interaction and toxicity of multi-chemical mixtures in environmental toxicology. We firstly conducted the acute immobilization tests with Daphnia magna exposed to mixtures of diazinon (DZN), fenitrothion (MEP); and thiobencarb (TB) in single, binary, and ternary formulations, and then fitted the results to the AFT model. The 48-h EC50 (concentration required to immobilize 50% of the daphnids at 48h) values for each pesticide obtained from the AFT model are within a factor of 2 of the corresponding values calculated from the single pesticide exposure tests, indicating the methodology is able to provide credible toxicity values. The AFT model revealed either significant synergistic (DZN and MEP; DZN and TB) or antagonistic (MEP and TB) interactions in binary mixtures, while the interaction pattern of ternary mixture depended on both the concentration levels and concentration ratios of pesticides. With a factor of 2, the AFT model accurately estimated the toxicities for 78% of binary mixture formulations that exhibited significant synergistic effects, and the toxicities for all the ternary formulations. Our results showed that the AFT model can provide a simple and efficient way to quantify the interactions between pesticides and to assess the toxicity of their mixtures. This ability may greatly facilitate the ecotoxicological risk assessment of exposure to multi-chemical mixtures.

Effects of neonicotinoid insecticide formulations and their components on Daphnia magna – the role of active ingredients and co-formulants

ABSTRACTFormulating agents used in pesticide products have been regarded as inactive/inert components; however, several studies confirmed additive, synergistic or antagonistic effects between the active ingredients (AIs) and additives, or the individual toxicity of the formulating agents. The worldwide used neonicotinoid insecticides and their components can reach surface waters, due to their physico-chemical properties (e.g. water solubility) or improper application in chemical plant protection technology, and can adversely affect non-target aquatic organisms. Formulated pesticides were analysed for alkane sulphonate surfactants by using liquid chromatography coupled with tandem mass spectrometry. In acute immobilisation tests on Daphnia magna, differences were found among the toxicity of the investigated neonicotinoid AIs and formulations. The toxicity of a formulated insecticide (Apache 50 WG®– AI: clothianidin) was found to be 46.5 times more toxic than explained by its AI, probably due to toxic effect of the formulating agents on D. magna. In contrast, two preparations (Calypso 480SC® – AI: thiacloprid, Actara 240 SC®– AI: thiamethoxam) were 2–3 times less toxic than their AIs. Results indicate possible synergistic/antagonistic interaction with the AIs.

Evaluation of the detoxification efficiencies of coking wastewater treated by combined anaerobic-anoxic-oxic (A2O) and advanced oxidation process

Coking wastewater contains many types of toxic and hazardous pollutants that have serious toxic effects on human beings as well as aquatic organisms. However, few studies have evaluated the detoxification efficiencies of the treatment processes that are extensively performed in operational coking wastewater treatment plants (WWTPs). This study investigates the detoxification efficiencies of a combined anaerobic-anoxic-oxic (A2O)-ozonation and A2O-Fenton oxidation process in two coking WWTPs using an acute immobilization test for Daphnia magna, acute toxicity test for adult zebrafish, embryo toxicity test for zebrafish and the comet assay. The raw coking wastewaters displayed high acute daphnia and fish toxicity, zebrafish embryo toxicity and genotoxicity. The A2O processing unit effectively removed acute and embryo toxicity, but not genotoxicity. In addition, the A2O effluent quality did not meet the integrated wastewater discharge standard in China (GB18918-2002). The ozonation and Fenton oxidation units used as post-treatments in these two plants not only treated the coking wastewater to the discharge standard but also reduced the genotoxicity. However, the final effluents still showed potential genotoxicity after high dilution. The results suggest that the discharge of treated coking wastewater probably poses potential risks to human health and the environment even if it met regulatory standards.

Assessing the environmental hazard of individual and combined pharmaceuticals: acute and chronic toxicity of fluoxetine and propranolol in the crustacean Daphnia magna.

Pharmaceuticals are widespread emerging contaminants and, like all pollutants, are present in combination with others in the ecosystems. The aim of the present work was to evaluate the toxic response of the crustacean Daphnia magna exposed to individual and combined pharmaceuticals. Fluoxetine, a selective serotonin re-uptake inhibitor widely prescribed as antidepressant, and propranolol, a non-selective β-adrenergic receptor-blocking agent used to treat hypertension, were tested. Several experimental trials of an acute immobilization test and a chronic reproduction test were performed. Single chemicals were first tested separately. Toxicity of binary mixtures was then assessed using a fixed ratio experimental design. Five concentrations and 5 percentages of each substance in the mixture (0, 25, 50, 75, and 100%) were tested. The MIXTOX model was applied to analyze the experimental results. This tool is a stepwise statistical procedure that evaluates if and how observed data deviate from a reference model, either concentration addition (CA) or independent action (IA), and provides significance testing for synergism, antagonism, or more complex interactions. Acute EC50 values ranged from 6.4 to 7.8 mg/L for propranolol and from 6.4 to 9.1 mg/L for fluoxetine. Chronic EC50 values ranged from 0.59 to 1.00 mg/L for propranolol and from 0.23 to 0.24 mg/L for fluoxetine. Results showed a significant antagonism between chemicals in both the acute and the chronic mixture tests when CA was adopted as the reference model, while absence of interactive effects when IA was used.

Effects of symbiotic bacteria on chemical sensitivity of Daphnia magna

The crustacean zooplankton Daphnia magna has been widely used for chemical toxicity tests. Although abiotic factors have been well documented in ecotoxicological test protocols, biotic factors that may affect the sensitivity to chemical compounds remain limited. Recently, we identified symbiotic bacteria that are critical for the growth and reproduction of D. magna. The presence of symbiotic bacteria on Daphnia raised the question as to whether these bacteria have a positive or negative effect on toxicity tests. In order to evaluate the effects of symbiotic bacteria on toxicity tests, bacteria-free Daphnia were prepared, and their chemical sensitivities were compared with that of Daphnia with symbiotic bacteria based on an acute immobilization test. The Daphnia with symbiotic bacteria showed higher chemical resistance to nonylphenol, fenoxycarb, and pentachlorophenol than bacteria-free Daphnia. These results suggested potential roles of symbiotic bacteria in the chemical resistance of its host Daphnia.

Ecotoxicological evaluation of chemical indicator substances present as micropollutants in laboratory wastewaters

<p>Laboratories produce a large volume of wastewaters containing different chemical indicators, organic species for which there is no complete knowledge about their effects in the aquatic environment.</p> <p>The aim of this work was to evaluate the ecotoxicity of four chemical indicator substances commonly used in titrations (sodium diphenylamine-4-sulfonate, phenolphthalein, methyl orange, and eriochrome black T) by applying two distinct bioassays that evaluated the growth inhibition of the microalga <em>Chlorella vulgaris</em> and the acute immobilization of the microcrustacean <em>Daphnia magna</em>.</p> <p>All the indicators showed growth inhibition rates in the chronic test performed with the alga C. vulgaris. Only phenolphthalein and eriochrome black-T showed high immobilization rates on the acute test for D. magna. C. vulgaris showed higher sensitivity to the chemical indicators tested than D. magna. Eriochrome black T was the most toxic for both test organisms and, according to the effective concentration that causes inhibition on 50% of C. vulgaris population, it can be considered as “highly toxic to aquatic organisms”. Phenolphthalein and methyl orange may be classified as “toxic to aquatic organisms” and sodium diphenylamine-4-sulfonate is the least toxic, only being considered as “harmful”.</p> <p>This work increases the awareness of the hazardous effects of these chemical indicators and reinforces the need of improved solutions to manage and treat laboratory effluents.</p>

The UV/peroxymonosulfate process for the mineralization of artificial sweetener sucralose

As one of non-nutritive and commonly used artificial sweeteners, sucralose (SUC) is now ubiquitous and detected in aquatic environments, which has already been recognized as an emerging contaminant. The mineralization of SUC in aqueous media by UV/peroxymonosulfate (PMS) process is investigated herein. Influences of several operating parameters, including pH, oxidant concentration and initial SUC concentration, on SUC mineralization were evaluated. Changing the pH from 3 to 9 had a weak effect on the mineralization of SUC, but the mineralization efficiency dropped sharply at pH 11. Nearly complete mineralization (>95%) of SUC was achieved after 60min treatment with 3.780mM oxidant at neutral pH. Both hydroxyl and sulfate radicals were demonstrated to participate in the oxidation of SUC according to EPR analysis. Under neutral pH condition, the presence of inorganic anion such as Cl−, NO3− or NO2− exhibited a varied inhibition effect on the mineralization efficiency with the order being NO2−>NO3−>Cl−. Activated sludge inhibition tests and Daphnia magna acute immobilization tests were performed to evaluate the detoxification efficiency of the UV/PMS process. The by-products formed were identified using LC–MS technique and a possible pathway of SUC degradation was proposed. In summary, the obtained result provides meaningful information on the application of UV/PMS process for the mineralization of SUC or other artificial sweeteners.

Acute stress enhances the glutamatergic transmission onto basoamygdala neurons embedded in distinct microcircuits

Amygdala activation is known to be critical for the processing of stressful events in brain. Recent studies have shown that the projection neurons (PNs) in amygdala, although architecturally intermingled, are integrated into distinct microcircuits and thus play divergent roles in amygdala-related behaviors. It remains unknown how stress regulates the individual amygdala PNs embedded in distinct microcircuits. Here, by using retrograde tracing and electrophysiological recording in in vitro slices, we explored the modulation of acute immobilization stress (AIS) on the basoamygdala (BA) PNs projecting either to medial prefrontal cortex (mPFC) or elsewhere, which we designated as BA-mPFC and non-BA-mPFC PNs respectively. The results showed that in the control mice, both the excitatory and inhibitory postsynaptic currents (sEPSCs/sIPSCs) were comparable between these two subsets of BA PNs. The influences of AIS on sEPSCs and sIPSCs were overall similar between the two neuronal populations. It markedly increased the sEPSCs amplitude but left unaltered their frequency as well as the sIPSCs amplitude and frequency. Despite this, several differences emerged between the effects of AIS on the distribution of sEPSCs/sIPSCs frequency in these two groups of BA PNs. Similar changes were also observed in the sEPSCs/sIPSCs of the two PN populations from mice experiencing forced swimming stress. Their intrinsic excitability, on the other hand, was nearly unaltered following AIS. Our results thus suggest that acute stress recruit both BA-mPFC and non-BA-mPFC PNs mainly through enhancing the glutamatergic transmission they receive.

Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress

Drug addiction requires associative learning processes that critically involve hippocampal circuits, including the opioid system. We recently found that acute and chronic stress, important regulators of addictive processes, affect hippocampal opioid levels and mu opioid receptor trafficking in a sexually dimorphic manner. Here, we examined whether acute and chronic stress similarly alters the levels and trafficking of hippocampal delta opioid receptors (DORs). Immediately after acute immobilization stress (AIS) or one-day after chronic immobilization stress (CIS), the brains of adult female and male rats were perfusion-fixed with aldehydes. The CA3b region and the dentate hilus of the dorsal hippocampus were quantitatively analyzed by light microscopy using DOR immunoperoxidase or dual label electron microscopy for DOR using silver intensified immunogold particles (SIG) and GABA using immunoperoxidase. At baseline, females compared to males had more DORs near the plasmalemma of pyramidal cell dendrites and about 3 times more DOR-labeled CA3 dendritic spines contacted by mossy fibers. In AIS females, near-plasmalemmal DOR-SIGs decreased in GABAergic hilar dendrites. However, in AIS males, near-plasmalemmal DOR-SIGs increased in CA3 pyramidal cell and hilar GABAergic dendrites and the percentage of CA3 dendritic spines contacted by mossy fibers increased to about half that seen in unstressed females. Conversely, after CIS, near-plasmalemmal DOR-SIGs increased in hilar GABA-labeled dendrites of females whereas in males plasmalemmal DOR-SIGs decreased in CA3 pyramidal cell dendrites and near-plasmalemmal DOR-SIGs decreased hilar GABA-labeled dendrites. As CIS in females, but not males, redistributed DOR-SIGs near the plasmalemmal of hilar GABAergic dendrites, a subsequent experiment examined the acute affect of oxycodone on the redistribution of DOR-SIGs in a separate cohort of CIS females. Plasmalemmal DOR-SIGs were significantly elevated on hilar interneuron dendrites one-hour after oxycodone (3 mg/kg, I.P.) administration compared to saline administration in CIS females. These data indicate that DORs redistribute within CA3 pyramidal cells and dentate hilar GABAergic interneurons in a sexually dimorphic manner that would promote activation and drug related learning in males after AIS and in females after CIS.

Antioxidant Enzymes in Brain Cortex of Rats Exposed to Acute, Chronic and Combined Stress

The study deals with manganese superoxide dismutase, copper, zinc superoxide dismutase, and catalase activities in brain cortex of Wistar rats exposed to acute stress (immobilization or cold for 2 h), chronic stress (long-term isolation or long-term forced swimming for 21 days), or to combined chronic/acute stress. We observed that i) single episodes of acute stress by immobilization increased activity of both superoxide dismutases; ii) both types of chronic stresses significantly elevated activities of all examined enzymes; iii) chronic social isolation was a much stronger stressor than physical stress by swimming; iv) in animals pre-exposed to chronic isolation, additional stress by immobilization or cold significantly decreased previously elevated activities of all enzymes, while after chronic swimming, acute immobilization lowered only catalase activity. The obtained results indicate that stress conditions most probably altered the cell redox equilibrium, thus influencing the antioxidant response in brain cortex. Further investigation of neuronal prooxidant/antioxidant cellular conditions is needed to improve the prevention and treatment of various stress induced diseases.

Acute to chronic estimation of Daphnia magna toxicity within the QSAAR framework

We constructed models for acute to chronic estimation of the Daphnia magna reproductive toxicities of chemical substances from their Daphnia magna acute immobilization toxicities. The models combined the acute toxicities with structural and physicochemical descriptors. We used multiregression analysis and selected the descriptors for the models by means of a genetic algorithm. Of the best 100 models (as indicated by the lack of fit score), 90% included the following descriptors: acute toxicity (i.e. an activity parameter), distribution coefficient (log D) and structural indicator variables that indicate the presence of –NH2 attached to aromatic carbon and the presence of a chlorine atom. We compared the predictive abilities of five of these quantitative structure–activity–activity relationship (QSAAR) acute to chronic estimation models with the predictive ability of a simple linear regression model. The comparison revealed that inclusion of structural and physicochemical descriptors such as those in QSAAR models can improve models for extrapolation from acute to chronic toxicity. Our results also provide a QSAAR framework that is expected to be useful for the further development of chronic toxicity estimation models.

Chronic but not acute immobilization stress stably enhances hippocampal CA1 metabotropic glutamate receptor dependent Long-Term Depression

Acute stress has been shown to facilitate but not increase metabotropic glutamate receptor (mGluR) mediated Long-Term Depression (LTD) in the hippocampus. However, the effect of chronic stress on mGluR dependent LTD has not been investigated. Moreover, whether stress leads to a transient modification LTD threshold or a more stable change in synaptic plasticity needs to be addressed. In the present study, we have explored the effects of both a ten-day long and a single day immobilization stress protocol on mGluR-LTD at the CA3:CA1synapse in the hippocampus of adult male Sprague-Dawley rats, a day after applying stress. Bath application of the selective group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) promoted robust LTD in hippocampal slices from control (i.e. un-stressed) animals. Administration of immobility stress for two hours per day for ten days significantly elevated this LTD to a level almost twice that of control, when observed 24h following the last stress event. Acute stress i.e. a single day of two hours of immobilization, however, failed to significantly enhance LTD, 24h later. These results demonstrate for the first time, that repeated exposure to stress, but not a single stress event, is required to bring about a stable alteration in mGluR mediated synaptic plasticity.

Toxicity of three strobilurins (kresoxim-methyl, pyraclostrobin, and trifloxystrobin) on Daphnia magna.

Strobilurins constitute a new class of fungicides that is the most widely used in the world. The present study was conducted to investigate the aquatic toxicity of 3 common strobilurin fungicides (kresoxim-methyl, pyraclostrobin, and trifloxystrobin) to Daphnia magna. The neonate acute immobilization test showed that the 48-h 50% effective concentration (EC50) values of kresoxim-methyl, pyraclostrobin, and trifloxystrobin were 443.3 µg/L, 20.9 µg/L, and 23.0 µg/L, respectively. In addition, the 3 strobilurins significantly induced activity of the important detoxification enzyme glutathione S-transferase (GST) in D. magna, and there was a significant positive relationship between GST activity and immobility of D. magna after acute exposure. The 3 strobilurins showed higher toxicity to D. magna embryos, and the 48-h EC50 were 157.3 µg/L, 3.9 µg/L, and 1.7 µg/L for kresoxim-methyl, pyraclostrobin, and trifloxystrobin, respectively. The 21-d chronic test revealed that the strobilurins could also significantly affect the reproduction, development, and growth of D. magna at sublethal concentrations. The lowest-observed-effect concentrations of kresoxim-methyl, pyraclostrobin, and trifloxystrobin for reproduction were 20 µg/L, 0.15 µg/L, and 0.2 µg/L, respectively, which were close to environmental concentrations. The findings indicate that strobilurin fungicides are very toxic to D. magna and they are sufficient to cause harm to D. magna at environmentally relevant concentrations. Environ Toxicol Chem 2017;36:182-189. © 2016 SETAC.

Cardioprotective effect of a new glutamic acid derivative, glufimet, under conditions of acute immobilization and painful stress in animals of different ages

The effect of 24-hour immobilization and painful stress on myocardial contractility was studied in young (6-month), middle-aged (12-month) and old (24-month) female rats. A reduction of the functional heart reserves was revealed. This manifested itself in a lower growth of the myocardial contraction and relaxation rates (+dP/dt max and–dP/dt max), the left ventricular pressure (LVP), the maximum intensity of the functioning of the structures (MIFS) under conditions of increased pre- and afterload, and stimulation of the cardiac adrenergic receptors, which was especially pronounced in the group of 24-month-old rats. During the load tests, higher growth indicators of +dP/dt max,–dP/dt max, LVP, and MIFS were observed in animals of all age groups treated with glufimet at a dose of 29 mg/kg before and after stress; these indicators were most significant in older rats compared to young and middle-aged animals. A reference drug, Phenibut, improves the studied parameters equally in 6-, 12-, and 24-month-old females subjected to stress.

Altered expression of KCC2 in GABAergic interneuron contributes prenatal stress-induced epileptic spasms in infant rat

Long-term stress during pregnancy causes neurologic deficits to offspring with altered gamma-aminobutyric acid (GABA) system in the brain. However, it is not clear how prenatal stress affects the maturing GABAergic interneurons and the resulting abnormalities in infantile seizures. Here, we showed that prenatal stress alters the maturation of GABA inhibitory system using a seizure model induced by prenatal stress. Prenatal stress with betamethasone or acute immobilization stress (AIS) on gestational day 15 increased the seizure susceptibility to N-methyl-d-aspartate-triggered spasms on postnatal day 15. The expression of GABA was lower in the prenatally stressed group, which compromise the decrease of glutamate decarboxylase 67-immunopositive cells. Prenatal stress markedly decreased the expression of K+/Cl− co-transporter (KCC2) in the cortex. GABA induced membrane depolarization demonstrated prenatal stress models had significant higher membrane depolarization compared to control. GABA increased KCC2 expression in cultured cortex-containing slices. Taken together, our results showed that prenatal stress with betamethasone or AIS altered the maturation of GABAergic progenitors and resulted in the lack of GABA input, which in turn, decreased KCC2 expression and lowered seizure threshold. We conclude that delayed GABA excitatory/inhibitory shift would render the cortical neuronal circuit more susceptible to excitatory input in prenatal stress induced seizure.