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Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies.
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Over one century after its first military use on the battlefield, sulfur mustard (SM) remains a threatening agent. Due to the absence of an antidote and specific treatment, the management of SM-induced lesions, particularly on the skin and eyes, still represents a challenge. Current therapeutic management is mainly limited to symptomatic and supportive care, pain relief, and prevention of infectious complications. New strategies are needed to accelerate healing and optimize the repair of the function and appearance of damaged tissues. Hydrogels have been shown to be suitable for healing severe burn wounds. Because the same gravity of lesions is observed in SM victims, hydrogels could be relevant dressings to improve wound healing of SM-induced skin and ocular injuries. In this article, we review how hydrogel dressings may be beneficial for improving the wound healing of SM-induced injuries, with special emphasis placed on their suitability as drug delivery devices on SM-induced skin and ocular lesions.
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Our study aims at comparing in C57/Bl male mice, the impact of repeated injections of baclofen (an agonist of GABAB receptor) or diazepam (a benzodiazepine acting through a positive allosteric modulation of GABAA receptor) administered during the alcohol-withdrawal period on hippocampus-dependent memory impairments and brain regional glucocorticoid dysfunction after a short (1-week) or a long (4-week) abstinence. Hence, mice were submitted to a 6-month alcohol consumption (12%v/v) and were progressively withdrawn to water. Then, after a 1- or 4-weeks abstinence, they were submitted to a contextual memory task followed by measurements of corticosterone concentrations in the dorsal hippocampus (dHPC), the ventral hippocampus (vHPC) and the prefrontal cortex (PFC). Results showed that 1- and 4-week withdrawn mice exhibited a severe memory deficit and a significant abnormal rise of the test-induced increase of corticosterone (TICC) in the dHPC, as compared to water-controls or to mice still under alcohol consumption. Repeated daily systemic administrations of decreasing doses of diazepam (ranged from 0.5 to 0.12 mg/kg) or baclofen (ranged from 1.5 to 0.37 mg/kg) during the last 15 days of the withdrawal period, normalized both memory and TICC scores in the dHPC in 1-week withdrawn animals; in contrast, only baclofen-withdrawn mice showed both normal memory performance and TICC scores in the dHPC after a 4-week withdrawal period. In conclusion, the memory improvement observed in 4-week withdrawn mice administered with baclofen stem from the protracted normalization of glucocorticoid activity in the dHPC, a phenomenon encountered only transitorily in diazepam-treated withdrawn mice.
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Sulfur mustard (SM) is a chemical blistering warfare agent affecting multiple organs. SM is an ongoing chemical threat in addition to the accidental risk associated with World War I buried shells. As no specific treatments are available, only symptomatic therapies can be used. To test new medical countermeasures in standard laboratories, analogs such as 2-chloroethyl ethylsulfide (CEES) are currently used, although only a few studies compare its clinical effects with SM. In the present paper, skin lesions induced by SM and CEES are compared in terms of their macroscopic aspects, histology, and molecular biology to evaluate the pertinence of CEES as a SM analog. For this purpose, an in vivo model of CEES vapor exposure, similar to that of SM, is described in this paper. RESULTS: showed similar skin lesions with CEES and SM but with slight differences in the apparition delay and intensity of the lesions. Indeed, SM induced earlier, deeper, and stronger lesions. However, the same healing status was observed at the end of the study period (14 days). In conclusion, CEES appears a relevant analog of SM, leading to similar skin lesions. The CEES vapor exposure model therefore seems suitable for testing new medical countermeasures.
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Substâncias para a Guerra Química , Gás de Mostarda , Substâncias para a Guerra Química/toxicidade , Biologia Molecular , Gás de Mostarda/análogos & derivados , Gás de Mostarda/toxicidade , PeleRESUMO
Sulfur mustard, a chemical warfare agent known to be a vesicant of skin, readily diffuses in the blood stream and reaches internal organs. In the present study, we used the analog (2-chloroethyl)-ethyl-sulfide (CEES) to provide novel data on the systemic diffusion of vesicants and on their ability to induce brain damage, which result in neurological disorders. SKH-1 hairless mice were topically exposed to CEES and sacrificed at different time until 14 days after exposure. A plasma metabolomics study showed a strong systemic impact following a self-protection mechanism to alleviate the injury of CEES exposure. This result was confirmed by the quantification of specific biomarkers in plasma. Those were the conjugates of CEES with glutathione (GSH-CEES), cysteine (Cys-CEES) and N-acetyl-cysteine (NAC-CEES), as well as the guanine adduct (N7Gua-CEES). In brain, N7Gua-CEES could be detected both in DNA and in organ extracts. Similarly, GSH-CEES, Cys-CEES and NAC-CEES were present in the extracts until day14. Altogether, these results, based on novel exposure markers, confirm the ability of vesicants to induce internal damage following dermal exposure. The observation of alkylation damage to glutathione and DNA in brain provides an additional mechanism to the neurological insult of SM.
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Encéfalo/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Dano ao DNA/efeitos dos fármacos , Gás de Mostarda/análogos & derivados , Administração Cutânea , Animais , Substâncias para a Guerra Química/farmacocinética , Glutationa/metabolismo , Metabolômica , Camundongos , Camundongos Pelados , Gás de Mostarda/administração & dosagem , Gás de Mostarda/farmacocinética , Gás de Mostarda/toxicidade , Pele/metabolismo , Fatores de Tempo , Distribuição TecidualRESUMO
Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organisation for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) approach to the conjugate of CEES to glutathione and two of its metabolites: the cysteine and the N-acetylcysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid-phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetylcysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similar to SM, the results are promising for application to this toxic of interest.
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Substâncias para a Guerra Química/efeitos adversos , Glutationa/análogos & derivados , Guanina/análogos & derivados , Gás de Mostarda/análogos & derivados , Animais , Linhagem Celular , Substâncias para a Guerra Química/análise , Cromatografia Líquida de Alta Pressão/métodos , Exposição Ambiental/efeitos adversos , Glutationa/efeitos adversos , Guanina/efeitos adversos , Humanos , Queratinócitos/efeitos dos fármacos , Camundongos , Gás de Mostarda/efeitos adversos , Gás de Mostarda/análise , Pele/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos , Testes de Toxicidade/métodosRESUMO
We previously showed that an acute stress-induced an early corticosterone rise in the dorsal hippocampus (dHPC) and a delayed one in the ventral hippocampus (vHPC). Congruently, we hypothesized that the dHPC may influence the time-course evolution of poststress glucocorticoid rise in the vHPC. To probe this issue, we performed ibotenic acid lesions of the dHPC and measured by microdialysis the time-course evolution of corticosterone rise in the vHPC after an acute stress delivery. In nonstress condition, we showed that the dHPC lesion induced a significant increase of corticosterone both in plasma and in the vHPC. In addition, an acute stress (electric footshocks) induced a faster and more sustained corticosterone rise in the vHPC of dHPC-lesioned animals, as compared to sham-operated ones. This study provides new found evidence to the effect that the dHPC lesion alters the time-course evolution of corticosterone rise within the vHPC after stress.
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Corticosterona/metabolismo , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Fatores de Tempo , Animais , Glucocorticoides/efeitos adversos , Masculino , Transtornos da Memória/metabolismo , Camundongos Endogâmicos C57BL , Microdiálise/métodos , Lobo Temporal/metabolismoRESUMO
Cognitive and emotional disorders have been reported in veterans intoxicated with sulfur mustard (SM) a chemical weapon belonging to the category of vesicating agents. However, the intense stress associated with the SM intoxication may render difficult determining the exact role played by SM intoxication itself on the emergence and maintaining of cognitive disorders. Animal's model would allow overcoming this issue. So far, we presently investigated the cognitive and emotional impact of an acute cutaneous intoxication with CEES (2-chloroethyl ethyl sulfide), a SM analog in C57/Bl6 mice. Our study evidenced that up to 5days after a single acute neat CEES skin exposure, compared to controls, mice exhibited i) a significant increase in anxiety-like reactivity in an elevated plus-maze and in an open-field tasks and ii) an alteration of working memory in a sequential alternation task. In contrast, mice submitted to intoxication with a diluted CEES solution or hydrochloric acid (HCl) did not show any memory or emotional impairments. Given that, Our data shows that a single local cutaneous intoxication with neat CEES induced long-lasting cognitive and emotional pejorative effects, in accordance with the epidemiological observations in veterans. Thus, the single acute neat CEES cutaneous intoxication in mice could allow studying the sulfur mustard-induced cognitive and emotional disorders and their further counter-measures.
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Sintomas Afetivos/induzido quimicamente , Sintomas Afetivos/psicologia , Substâncias para a Guerra Química/toxicidade , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Gás de Mostarda/análogos & derivados , Administração Cutânea , Administração Tópica , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Dano ao DNA , Eritema/induzido quimicamente , Eritema/patologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Gás de Mostarda/administração & dosagem , Gás de Mostarda/toxicidade , Pele/patologiaRESUMO
This study intends to determine whether long-lasting glucocorticoids (GCs) dysregulation in the prefrontal cortex (PFC) or the dorsal hippocampus (dHPC) play a causal role in the maintenance of working memory (WM) deficits observed after alcohol withdrawal. Here, we report that C57/BL6 male mice submitted to 6 months alcohol consumption (12 percent v/v) followed by 1 (1W) or 6 weeks (6W) withdrawal periods exhibit WM deficits in a spatial alternation task and an exaggerated corticosterone rise during and after memory testing in the PFC but not the dHPC. In contrast, emotional reactivity evaluated in a plus-maze is altered only in the 1W group. No behavioral alterations are observed in mice still drinking alcohol. To determine the causal role of corticosterone in the withdrawal-associated long-lasting WM deficits, we further show that a single intraperitoneal injection injection of metyrapone (an inhibitor of corticosterone synthesis) 30 minutes before testing, prevents withdrawal-associated WM deficits and reestablishes PFC activity, as assessed by increased phosphorylated C-AMP Response Element-binding protein (CREB) immunoreactivity in withdrawn mice. Finally, we show that intra-PFC blockade of mineralocorticoid receptors by infusion of spironolactone and, to a lesser extent, of GCs receptors by injection of mifepristone reverses the WM deficits induced by withdrawal whereas the same injections into the dHPC do not. Overall, our study evidences that long-lasting GCs dysfunction selectively in the PFC is responsible for the emergence and maintenance of WM impairments after withdrawal and that blocking prefrontal mineralocorticoid receptors receptors restores WM in withdrawn animals.
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Alcoolismo/complicações , Corticosterona/sangue , Transtornos da Memória/induzido quimicamente , Memória de Curto Prazo/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Memória Espacial/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/complicações , Alcoolismo/sangue , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo , Masculino , Transtornos da Memória/sangue , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/sangueRESUMO
STUDY OBJECTIVES: Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex, but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the impact of connexins on the effects of modafinil using connexin inhibitors. METHODS: Modafinil was administered alone or combined with inhibitors of astrocyte connexin, meclofenamic acid, or flecainide, respectively, acting on Cx30 and Cx43. Sleep-wake states were monitored in wild-type and narcoleptic orexin knockout mice. A spontaneous alternation task was used to evaluate working memory in wild-type mice. The effects of the compounds on astroglial intercellular coupling were determined using dye transfer in acute cortical slices. RESULTS: Meclofenamic acid had little modulation on the effects of modafinil, but flecainide enhanced the wake-promoting and pro-cognitive effects of modafinil. Co-administration of modafinil/flecainide resulted in a marked decrease in the number and duration of direct transitions to rapid eye movement sleep, which are characteristic of narcoleptic episodes in orexin knockout mice. Furthermore, modafinil enhanced the connexin-mediated astroglial cell coupling, whereas flecainide reduced it. Finally, this modafinil-induced effect was reversed by co-administration with flecainide. CONCLUSIONS: Our study indicates that flecainide impacts the pharmacological effects of modafinil, likely through the normalization of Cx30-dependent gap junctional coupling in astroglial networks. The enhancement of the wake-promoting, behavioral, and cognitive outcomes of modafinil demonstrated here with flecainide would open new perspectives in the management of sleep disorders such as narcolepsy. COMMENTARY: A commentary on this article appears in this issue on page 1175.
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Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Compostos Benzidrílicos/farmacologia , Conexina 43/metabolismo , Conexinas/metabolismo , Animais , Astrócitos/citologia , Compostos Benzidrílicos/administração & dosagem , Conexina 30 , Conexina 43/antagonistas & inibidores , Conexinas/antagonistas & inibidores , Modelos Animais de Doenças , Flecainida/farmacologia , Masculino , Ácido Meclofenâmico/farmacologia , Camundongos , Camundongos Knockout , Modafinila , Narcolepsia/tratamento farmacológico , Narcolepsia/genética , Narcolepsia/patologia , Narcolepsia/fisiopatologia , Orexinas/deficiência , Orexinas/genética , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacosRESUMO
INTRODUCTION: The emergence of normobaric devices for hypoxia awareness training makes crucial the study of physiological and cognitive effects induced by acute normobaric hypoxia (NH) exposure. Our study aimed to 1) investigate the effects of acute NH exposure on physiological variables and working memory; and 2) investigate the physiological and cognitive effects of oxygen breathing before and after acute NH exposure. METHODS: There were 86 healthy men who were randomized into 4 groups: the Normoxia-Air group (N = 23), whose subjects were breathing air; the Hypoxia-Air group (N = 22), where NH exposure was preceded and followed by air breathing; the Normoxia-O2group (N = 21), whose protocol was similar to the Normoxia-Air group, except with the addition of 100% O2breathing periods; and the Hypoxia-O2group (N = 20), whose participants were exposed to 100% O2before and after NH exposure. Working memory was assessed with the Paced Auditory Serial Addition Test. Peripheral oxygen saturation (Spo2), heart rate (HR), and electroencephalogram (EEG) were recorded. RESULTS: Acute NH exposure induced a classical physiological response (i.e., decreased Spo2and increased HR), but not identical to the well-described physiological response to acute hypobaric hypoxia. Acute NH also caused a strong impairment in working memory. Oxygen breathing following NH exposure induced a slowing in the EEG associated with a worsening of working memory performance. DISCUSSION: Acute NH exposure revealed a good surrogate for the classical hypobaric chamber for refresher hypoxia awareness training. Because the association between hypoxia and hyperoxia seems deleterious for the brain, we suggest that NH exposure should be surrounded by air breathing.
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Cognição/fisiologia , Hipóxia/fisiopatologia , Oxigênio/metabolismo , Adulto , Eletroencefalografia , Voluntários Saudáveis , Frequência Cardíaca/fisiologia , Humanos , MasculinoRESUMO
Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hippocampo-prefrontal cortex interplay. The role of the stress-induced regional corticosterone increase in such dysfunction remains however unclear, since there is no published study as yet dedicated to measuring corticosterone concentrations simultaneously in both the prefrontal cortex (mPFC) and the hippocampus (dHPC) in relation with memory impairments. To that aim, we first showed in Experiment 1 that an acute stress (3 electric footschocks; 0.9 mA each) delivered before memory testing reversed the memory retrieval pattern (MRP) in a serial discrimination task in which mice learned two successive discriminations. More precisely, whereas non-stressed animals remembered accurately the first learned discrimination and not the second one, stressed mice remembered more accurately the second discrimination but not the first one. We demonstrated that local inactivation of dHPC or mPFC with the anesthetic lidocaine recruited the dHPC activity in non-stress conditions whereas the stress-induced MRP inversion recruited the mPFC activity. In a second experiment, we showed that acute stress induced a very similar time-course evolution of corticosterone rises within both the mPFC and dHPC. In a 3rd experiment, we found however that in situ injections of corticosterone either within the mPFC or the dHPC before memory testing favored the emergence of the mPFC-dependent MRP but blocked the emergence of the dHPC-dependent one. Overall, our study evidences that the simultaneous increase of corticosterone after stress in both areas induces a shift from dHPC (non-stress condition) to mPFC-dependent MRP and that corticosterone is critically involved in mediating the deleterious effects of stress on cognitive functions involving the mPFC-HPC interplay.
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INTRODUCTION: During an acute hypoxia exposure, impairment of memory is one of the most frequently reported symptoms, either during hypoxia awareness training of aircrews or after an in-flight hypoxic incident. However, the effects of acute hypoxia on memory have been little studied in laboratory-controlled conditions. Moreover, none of these studies were performed in hypobaric conditions. The main aim of our study was to investigate the effects of acute hypobaric hypoxia on working memory (WM). This study also aimed to find links between physiological measurements and cognitive performance during acute hypoxia exposure. METHODS: During hypoxia awareness training, 28 subjects (experimental group) were exposed to a simulated altitude level of 10,000 m (31,000 ft) in a hypobaric chamber, while 29 subjects (control group) stayed at sea level. WM was assessed in both groups with the Paced Auditory Serial Addition Test (PASAT). Peripheral oxygen saturation (SpO2) and heart rate were recorded. RESULTS: WM was strongly impaired in the hypoxic group. One major finding is that hypoxia highly increased the mean error frequency rate. WM performance decreased linearly with hypoxemia, but SpO2 was weakly predictive of PASAT performance and vice versa. DISCUSSION: WM is impaired by acute hypobaric hypoxia. Given the importance of WM in aircraft piloting and its sensitivity to hypoxia, the PASAT, in association with SpO2 and EEG recordings, could improve both hypoxia training and our understanding of the effects of hypoxia on memory.
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Doença da Altitude/fisiopatologia , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/fisiologia , Adulto , Medicina Aeroespacial , Câmaras de Exposição Atmosférica , Frequência Cardíaca/fisiologia , Humanos , Masculino , Testes Neuropsicológicos , Oxigênio/sangueRESUMO
We aimed at demonstrating that corticosteroid binding globulin (CBG), a plasma glycoprotein binding glucocorticoids with high affinity in blood, endorses a major role under stress conditions by regulating free glucocorticoid access to the brain and thereby influences glucocorticoid-dependent behaviors. Hence, we compared CBG-deficient mice (Cbg-/-) and their controls (Cbg+/+) in a specific memory task, i.e. the delayed alternation behavior, requiring memory retrieval both under stress and nonstress conditions and previously shown to be dependent on hippocampal glucocorticoid levels. Our results evidence that Cbg-/- mice, unlike controls, remain insensitive to stress applied before memory retrieval. Furthermore, under stress conditions, we observed a blunted surge of corticosterone (CORT) in plasma and no free CORT rise in the hippocampus of Cbg-/-. Moreover, intrahippocampal infusion of CORT through implanted cannulae was used to mimic stress CORT rise before memory retrieval. This infusion of CORT reproduced memory retrieval impairments in Cbg-/- as in Cbg+/+ controls. Finally, we provide evidence that Cbg-/- mice exhibit a normal adrenal response to stress and ACTH. Given that CBG deficiency is known to markedly impact on CORT clearance from plasma, our current article demonstrates that Cbg-/- insensitivity in memory retrieval after stress results from the blunted CORT response due to increased CORT clearance. Overall, our data suggest that the impact of CBG genetic deficiency on various behavioral patterns reported previously stems from a smaller CORT reservoir in blood. Inasmuch as CBG discloses interindividual variations, such a parameter ought to be taken into account when studying stress-induced glucocorticoid action in brain.
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Corticosterona/farmacologia , Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Transcortina/genética , Glândulas Suprarrenais/metabolismo , Animais , Corticosterona/sangue , Expressão Gênica , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Knockout , Transporte Proteico , Estresse Psicológico/metabolismo , Transcortina/metabolismoRESUMO
This study was aimed at determining the type of the glucocorticoid membrane receptors (mineralocorticoid receptors (MRs) or glucocorticoid receptors (GRs)) in the dorsal hippocampus (dHPC) involved in the rapid effects of corticosterone or stress on memory retrieval. For that purpose, we synthesized corticosterone-3-O-carboxymethyloxime-bovine serum albumin conjugate (Cort-3CMO-BSA) conjugate (a high MW complex that cannot cross the cell membrane) totally devoid of free corticosterone, stable in physiological conditions. In a first experiment, we evidenced that an acute stress (electric footshocks) induced both a dHPC corticosterone rise measured by microdialysis and memory retrieval impairment on delayed alternation task. Both the endocrinal and cognitive effects of stress were blocked by metyrapone (a corticosterone synthesis inhibitor). In a second experiment, we showed that bilateral injections of either corticosterone or Cort-3CMO-BSA in dHPC 15 min before memory testing produced impairments similar to those resulting from acute stress. Furthermore, we showed that anisomycin (a protein synthesis inhibitor) failed to block the deleterious effect of Cort-3CMO-BSA on memory. In a third experiment, we evidenced that intra-hippocampal injection of RU-28318 (MR antagonist) but not of RU-38486 (GR antagonist) totally blocked the Cort-3CMO-BSA-induced memory retrieval deficit. In a fourth experiment, we demonstrated that RU-28318 administered 15 min before stress blocked the stress-induced memory impairments when behavioral testing occurred 15 min but not 60 min after stress. Overall, this study provides strong in vivo evidence that the dHPC membrane GRs, mediating the rapid and non-genomic effects of acute stress on memory retrieval, are of MR but not GR type.
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Corticosterona/metabolismo , Hipocampo/fisiopatologia , Transtornos da Memória/fisiopatologia , Receptores de Glucocorticoides/fisiologia , Receptores de Mineralocorticoides/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Corticosterona/análogos & derivados , Corticosterona/farmacologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Soroalbumina Bovina/farmacocinética , Estresse Psicológico/complicações , Estresse Psicológico/metabolismoRESUMO
Benzodiazepines (BDZ) are widely prescribed in the treatment of anxiety disorders associated to aging. Interestingly, whereas a reciprocal interaction between the GABAergic system and HPA axis has been evidenced, there is to our knowledge no direct evaluation of the impact of BDZ on both hippocampus (HPC) corticosterone concentrations and HPC-dependent memory in stressed middle-aged subjects. We showed previously that an acute stress induced in middle-aged mice severe memory impairments in a hippocampus-dependent task, and increased in parallel hippocampus corticosterone concentrations, as compared to non-stressed middle-aged controls (Tronche et al., 2010). Based on these findings, the aims of the present study were to evidence the impact of diazepam (a positive allosteric modulator of the GABA-A receptor) on HPC glucocorticoids concentrations and in parallel on HPC-dependent memory in acutely stressed middle-aged mice. Microdialysis experiments showed an interaction between diazepam doses and corticosterone concentrations into the HPC. From 0.25 to 0.5 mg/kg, diazepam dose-dependently reduces intra-HPC corticosterone concentrations and in parallel, dose-dependently increased hippocampal-dependent memory performance. In contrast, the highest (1.0 mg/kg) diazepam dose induces a reduction in HPC corticosterone concentration, which was of greater magnitude as compared to the two other diazepam doses, but however decreased the hippocampal-dependent memory performance. In summary, our study provides first evidence that diazepam restores in stressed middle-aged animals the hippocampus-dependent response, in relation with HPC corticosterone concentrations. Overall, our data illustrate how stress and benzodiazepines could modulate cognitive functions depending on hippocampus activity.
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Increasing numbers of reports have substantiated to date, a beneficial influence of cytokine treatment on neurogenesis processes in damaged rodent brains. Most of these investigations further revealed that cytokine treatment induces either partial or full recovery of cognitive behavior impaired by cerebral lesions. Hence, we investigated the effects of a cytokine treatment on neuronal regeneration and cognitive behavior in mice subjected to nerve agent exposure. Subcutaneous injection of a mixture of 40 µg/kg fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) was administered daily over 8 days to soman-poisoned mice (1.2 LD50 soman). Memory performances (T-maze and Morris water maze) and emotional behavior (elevated plus maze; auditory and contextual response in a fear conditioning task) were assessed on post-soman days 30 and 90. Brains were collected on post-soman days 9, 30 and 90 so as to perform NeuN-immunohistochemistry in the hippocampus and amygdala (neuronal regeneration quantification). Following soman-induced brain lesions, a spontaneous neuronal regeneration occurred in both the hippocampus and amygdala. Cytokine treatment enhanced neuronal regeneration in the hippocampus however not in the amygdala. Soman poisoning fostered altogether memory impairments as well as anxiety or fear-like behavioral disturbances in mice. A spontaneous recovery of standard emotional behavior occurred overtime. Such a recovery displayed significantly enhanced speed under cytokine treatment. Unfortunately, no memory performance recovery was evidenced in soman-intoxicated mice whether treated or not with cytokines.
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Inibidores da Colinesterase/intoxicação , Transtornos Cognitivos/tratamento farmacológico , Fator de Crescimento Epidérmico/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Soman/intoxicação , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Transtornos Cognitivos/fisiopatologia , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Fator de Crescimento Epidérmico/administração & dosagem , Fator de Crescimento Epidérmico/farmacologia , Medo/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Fator 2 de Crescimento de Fibroblastos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismoRESUMO
The aim of the present work was to investigate in mice the effects of a total 10-hr sleep deprivation on contextual (episodic-like) and spatial (reference) memory tasks. For that purpose, mice learned two consecutive discriminations (D1 and D2) in a 4-hole board involving either identical (Serial Spatial Discrimination, SSD) or distinct (Contextual Serial Discrimination, CSD) internal contextual cues. In a second step, we intended to assess the corrective effect of modafinil on memory impairments generated by sleep deprivation. Sleep deprivation was triggered through an alternative platform apparatus (water box), previously validated using EEG recording and spectral analysis. We showed that a 10-hr total sleep deprivation impaired the CSD task but not the SSD one. Moreover, the impairment of contextual memory in sleep-deprived animals was dose-dependently corrected by modafinil. Indeed, modafinil administered after the sleep deprivation period and 30 min before the test session restored a memory retrieval pattern identical to non sleep-deprived animals at the doses of 32 and 64 mg/kg, however not at 16 mg/kg. Results hereby evidence that the vigilance-enhancing drug modafinil is able to restore the contextual memory performance at a low dose as compared to other memory tasks, possibly by an enhancement of hippocampal activity known to be both involved in the processing of contextual information and impaired following our sleep deprivation procedure.
Assuntos
Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Memória , Privação do Sono , Animais , Comportamento Animal , Corticosterona/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , ModafinilaRESUMO
OBJECTIVE: We study the effect of short half-life hypnotics (zaleplon or zolpidem against placebo) on altitude tolerance in 12 nonacclimated male soldiers (age, 22.1 +/- 0.8 years; height, 177.8 +/- 1.7 cm; weight, 69.8 +/- 1.7 kg). METHODS: Soldiers were trained to practice mountaineering at high altitude (2,533-4,810 meters) during 3 periods (one per medication tested) of 4 days (D1-D4). In each period the nights were spent in a hut (3,613 m). Administration of hypnotics or placebo was then implemented at 9:45 p.m. Nocturnal arterial oxygen saturation (SaO2) and heart rate variability (HRV) were monitored. At 5:00 a.m. and 9:00 p.m. physical fitness was assessed using acute mountain sickness (AMS) score. At 5:00 p.m., a posteffort stand test was carried out to evaluate the orthoparasympathetic imbalance with fatigue. RESULTS: Nocturnal SaO2 correlated negatively with morning AMS scores (R = -0.820, p < 0.02) and HRV analysis favored the sympathetic modulation. Posteffort stand tests revealed that sympathetic modulation attenuated from D2 to D3 in treated groups. CONCLUSION: The present study provides evidence that zolpidem or zaleplon improves sleep and subsequent physical fitness at altitude.
Assuntos
Acetamidas/farmacocinética , Doença da Altitude/prevenção & controle , Hipnóticos e Sedativos/farmacocinética , Militares , Montanhismo/fisiologia , Aptidão Física/fisiologia , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Acetamidas/administração & dosagem , Análise de Variância , Meia-Vida , Frequência Cardíaca/fisiologia , Humanos , Hipnóticos e Sedativos/administração & dosagem , Modelos Lineares , Masculino , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Suíça , Adulto Jovem , ZolpidemRESUMO
This study examines the effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on serial contextual memory retrieval in non-stress and stress conditions. Independent groups of mice learned two successive contextual serial discriminations (D1 and D2) in a four-hole board. The discriminations differed each by the color and texture of the floor. Twenty-four hours later, memory testing occurred in independent groups of mice on one of the two floors of the initial acquisition session. Half of the subjects received three electric footschocks (0.9mA, 2s) 5min prior to testing. Results showed that (i) stress induced a plasma corticosterone rise of same magnitude in sham-operated and MD-lesioned mice; (ii) non-stressed sham-operated mice accurately remembered D1 but not D2, whereas stressed sham-operated animals remembered D2 but not D1; (iii) non-stressed MD-lesioned mice exhibited a memory retrieval pattern similar to that observed in non-stressed sham-operated mice; (iv) however, the stress-induced inversion of the memory retrieval pattern was not observed in MD animals. The effects of MD lesions on memory retrieval in this task are similar to those observed in earlier studies in prefrontal cortex or amygdala-lesioned mice [Chauveau F, Piérard C, Coutan M, Drouet I, Liscia P, Béracochéa D. Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory pattern in mice. Neurobiol Learn Mem 2008;90:395-403]; they are however in sharp contrast with mice exhibiting hippocampal lesions [Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress condition. Neurobiol Learn Mem; in press; Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus; in press]. Overall, the present findings highlight the involvement of the MD in an AMG/PFC system mediating the rapid effects of stress on serial memory retrieval.