A esquizofrenia continua sendo um dos transtornos mais desafiadores para a clínica psiquiátrica, apesar dos estudos atuais que tentam elucidar sua fisiopatologia e buscar novas opções de tratamento. A n-acetilcisteína (NAC) é uma droga utilizada há mais de 30 anos na clínica médica no tratamento da intoxicação por acetaminofeno e como mucolítico na DPOC, entre outros. Evidências recentes apoiam o seu uso no tratamento de diversos transtornos neuropsiquiátricos, como depressão, transtorno afetivo bipolar, dependência química e esquizofrenia. A droga tem como provável mecanismo de ação um aumento na atividade antioxidante através do aumento nos níveis de glutationa (GSH) e modulação da neurotransmissão glutamatérgica. Nas duas últimas décadas, o estudo dos mecanismos neurobiológicos subjacentes aos transtornos psiquiátricos, bem como a investigação dos possíveis mecanismos e regiões cerebrais influenciados por substâncias psicofarmacológicas, recebeu importante contribuição das técnicas de neuroimagem funcional. Apesar disto, até o momento existem poucos estudos que avaliaram os mecanismos centrais relacionados às propriedades antipsicóticas da NAC em humanos. Este estudo tem o objetivo de investigar os efeitos da NAC em indivíduos portadores de esquizofrenia refratária em uso exclusivo de clozapina através de medidas de sintomas positivos e negativos e da avaliação da perfusão cerebral através de ressonância magnética nuclear utilizando a técnica de arterial spin labeling (ASL). Foram avaliados 20 sujeitos com esquizofrenia refratária em uso de clozapina em um estudo com distribuição aleatória, duplo-cego e controlado por placebo, utilizando a dose de 2000mg por dia de NAC. Do total da amostra, 14 tiveram as imagens perfusão sanguínea cerebral analisadas. O estudo teve a duração de oito semanas, com avaliações a cada quatro semanas e realização das RMN no início e ao final do período. Não foram observadas diferenças estatisticamente significativas entre os grupos placebo e NAC nas escalas BPRS e PANSS-N. O grupo que recebeuNAC apresentou mais efeitos colaterais, porém no geral a medicação foi bem tolerada. Também não se observou diferenças no FSC das diversas ROI analisadas. A NAC não produziu mudanças estatisticamente significativas nas escalas de sintomas e no FSC nesta amostra, apesar de outros estudos mostrarem diferenças significativas favorecendo a NAC. O presente estudo não mostrou melhora do FSC, mesmo após oito semanas, o que pode significar que a ASL pode não ser um método adequado para avaliar os efeitos cerebrais desta droga / Schizophrenia continues to be one of the most challenging psychiatric disorders in the clinical practice, despite recent studies that attempt to elucidate its pathophysiology and search for new treatment options. N-acetylcysteine (NAC) is a drug that has been used for more than 30 years in clinical medicine, in situations like acetaminophen intoxication and as mucolytic in COPD, among others. Recent studies support its therapeutic use in neuropsychiatric disorders such as depression, bipolar disorder, substance abuse and schizophrenia. The mechanism of action of NAC seems to occur in antioxidant activity, through the increase of glutathione levels (GSH) and in the modulation of glutamatergic neurotransmission. In the last two decades, the study of the neurobiological mechanisms underlying psychiatric disorders, as well as the investigation of the possible mechanisms and brain areas influenced by psychopharmacological substances received a significant contribution of functional neuroimaging techniques. Despite this, there are few studies that have evaluated the central mechanisms related to the antipsychotic properties of NAC in humans. This study aims to investigate the effects of NAC in subjects with refractory schizophrenia, exclusively on clozapine use, through measure of positive and negative symptoms and the evaluation of cerebral perfusion by magnetic resonance imaging, using the arterial spin labeling technique (ASL) . Twenty subjects with refractory schizophrenia were evaluated in a randomized, double-blind, placebo-controlled study using a dose of 2000mg per day of NAC. From the total sample, 14 had cerebral perfusion images analyzed. The study had a duration of eight weeks, with evaluations at each four weeks and MRI sessions before the beginning of NAC and at the end of the period. The results did not show statistically significant differences between placebo and NAC groups onthe BPRS and PANSS-N scales. The NAC group presented more side effects, although the medication was well tolerated in general. There were also no differences in the cerebral blood flow (CBF) among the regions of interest analyzed. Although there was no difference regarding symptoms scales the CBF in this sample, other studies found differences favoring NAC. The present study did not show changes of the CBF, which might mean that ASL is not an adequate technic to evaluate neurochemical effects of this drug

Introduction: Triple A syndrome (AAAS) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and progressive neurodegeneration. Increased oxidative stress, demonstrated in patients’ fibroblasts in vitro, may be a central disease mechanism. N-acetylcysteine protects renal function in patients with kidney injuries associated with increased oxidative stress and improves viability of AAAS-knockdown adrenal cells in vitro. Patient and Results: A boy diagnosed with AAAS presented with short stature and increased oxidative stress in vivo assessed by increased thiobarbituric acid reactive substances (TBARS), which are markers of lipid peroxidation, and by the susceptibility of LDL to oxidation and the capacity of HDL to prevent it. A homozygous missense germline mutation (c.523G>T, p.Val175Phe) in AAAS was identified. N-acetylcysteine (600 mg orally, twice daily) decreased oxidative stress but did not change the patient’s growth pattern. Conclusions: An increase in oxidative stress is reported for the first time in vivo in an AAAS patient. N-acetylcysteine was capable of decreasing TBARS levels, reducing the susceptibility of LDL to oxidation and improving the antioxidant role of HDL. The longterm effect of antioxidant treatment should be evaluated to determine the real benefit for the prevention of the degenerative process in AAAS.

Objectifs Aucun agent n’a été approuvé pour prévenir l’ototoxicité secondaire au cisplatin. Nos objectifs consistaient à évaluer la protection auditive offerte par le lactate et le N-acétylcystéine (NAC) intra-tympaniques après injection de cisplatin, ainsi que l’absorption systémique du NAC intra-tympanique. Méthodes Seize cochons d’inde formaient 2 groupes ayant reçu une solution de lactate et de NAC à 20% dans l’oreille testée. L’oreille contro-latérale a reçu une solution saline contrôle. Après 30 minutes, une injection intrapéritonéale de 3 mg/kg de cisplatin a été effectuée et répétée une fois par semaine jusqu’à une dose finale de 24 mg/kg. Les potentiels évoqués auditifs du tronc cérébral (PEATC) ont été mesurés avant les injections, après 9 mg/kg et 24 mg/kg de cisplatin. Les cochlées ont été analysées au microscope électronique à balayage. La diffusion systémique du NAC a été évaluée par chromatographie en phase liquide. Résultats Pour les oreilles contrôles, les seuils auditifs des PEATC ont augmenté uniformément sur toutes les fréquences (28,4 dB en moyenne). Le groupe lactate montrait une augmentation moins importante (17,0 dB). Les basses fréquences étaient nettement moins affectées. Le groupe NAC a subi une augmentation des seuils de 89 dB. La microscopie électronique a démontré une préservation partielle des cellules ciliées externes des cochlées traitées au lactate et une destruction complète de celles traitées au NAC. La chromatographie n’a démontré aucune diffusion de NAC. Conclusions Le lactate offre une protection partielle significative contre l’ototoxicité induite par le cisplatin. Les injections de NAC n’offrent pas de protection lorsque administrées en concentrations élevée. Le NAC intra-tympanique ne se diffuse pas systémiquement. / Objectives There is no approved agent to prevent cisplatin-induced ototoxicity. Our objectives are to identify and compare the protective effect of intratympanic injections of lactate or N-acetylcysteine (NAC) in the prevention of cisplatin-induced ototoxicity and to study systemic diffusion of intratympanic NAC. Methods Sixteen guinea pigs, forming two groups, received respectively intratympanic lactate and 20% NAC in one ear. The contra-lateral ears received a control saline solution. After 30 minutes, an intra-peritoneal cisplatin injection of 3 mg/kg was performed and repeated once a week to achieve a final dose of 24mg/kg. Auditory brainstem responses (ABR) were recorded before any injection, after 9mg/kg and after 24mg/kg of cisplatin for the frequencies 2, 4, 6 and 8kHz. Cochleas were analyzed under scanning electron microscope. Systemic diffusion of NAC was studied using high performance liquid chromatography. Results For the control ears, ABR thresholds increased uniformly by an average of 28.4dB. The lactate group showed a lower threshold increase by an average of 17.0dB. The NAC showed an important threshold increase of 89.0dB. Lactate showed a significant hearing protection at 2000Hz (p<0.01). Electron microscopy revealed partial preservation of cochlear outer hair cells stereocilia for the ears treated with lactate and severe disruption for NAC group. No systemic diffusion of NAC was observed with chromatography. Conclusion Lactate offers significant partial protection against cisplatin-induced ototoxicity. NAC does not offer any protection when administered in high concentrations. Intratympanic NAC does not diffuse systemically.

Introdução: Wistar Audiogenic Rats (WAR) é modelo experimental desenvolvido na Faculdade de Medicina de Ribeirão Preto, para estudo da epilepsia, entretanto, a seleção genética em resposta aos comportamentos de crises audiogênicas também trouxe à tona alterações no metabolismo energético nesses animais. Dois estudos são relevantes deste ponto de vista, no primeiro Botion e Doretto observaram que WAR após serem estimulados apresentam: (a) valores de glicemia maior em relação ao Wistar; (b) aumento no lactato circulante - o que pode indicar deficiência na fosforilação oxidativa (OXPHOS); (c) aumento da atividade adrenérgica, induzindo dessensibilização da via lipolítica ?-adrenérgica no tecido adiposo epididimal. Pereira e colaboradores investigando o metabolismo de carboidratos relataram: (a) aumento na via glicólica; (b) translocação de GLUT4 aumentada no músculo gastrocnêmico e (c) redução nos níveis de glicogênio muscular. Objetivo: Diante desses achados o presente estudo tem como objetivo elucidar o metabolismo energético mitocondrial e sua relação com as crises epiléticas induzidas por estímulos sonoros. Resultados: Através de analises comportamentais e calorimetria indireta, relatamos que WAR possui perfil ansiogênico e tem preferência em oxidar aminoácidos; utilizando biopsias de tecido hepático, musculo esquelético e cardíaco, observamos maior densidade mitocondrial, acompanhada de maior geração de H2O2 e como consequência maior estresse oxidativo; na busca para elucidar com maior destreza, realizamos isolamento da fração mitocondrial do tecido hepático, e concluímos que não há maior geração de H2O2 por mitocôndria, porém há um enriquecimento proteico (algumas proteínas funcionais - como as envolvidas na OXPHOS- e outras não-funcionais - como as UCPs), além de relatarmos maiores níveis de proteínas envolvidas na dinâmica mitocondrial, desse modo podemos concluir que WAR possuem maior densidade mitocondrial e mitocôndrias com maior eficiência; o mesmo perfil mitocondrial foi observado no tecido cerebral. Após tratamento com DNP e NAC, observamos redução do estresse oxidativo no tecido cerebral, porém apenas NAC reduziu a severidade da crise, assim concluímos que o suave desacoplamento induzido por DNP não é capaz de reduzir de forma significativa a severidade da crise, porém a inibição da glicólise pelo NAC, alterou a bioenergética cerebral é capaz a reduzir a severidade da crise, deixando evidenciado que o metabolismo energético tem papel essencial/relevante na crise epilética induzida por estímulos sonoros em WAR, enquanto o estresse oxidativo tem papel secundário. / Introduction: Wistar Audiogenic Rats (WAR) is an experimental model developed in the Ribeirão Preto Medical School, for the study of epilepsy, however, the genetic selection in response to the behaviors of audiogenic crisis also brought up changes in energy metabolism in these animals. Two studies are relevant from this point of view, in the first Botion and Doretto observed that WAR after being stimulated present: (a) higher blood glucose values in relation to the Wistar; (b) Increase in circulating lactatewhich may indicate deficiency in oxidative phosphorylation (OXPHOS); (c) Increased adrenergic activity. Pereira and collaborators investigating the metabolism of carbohydrates reported: (a) increase in glycolysis; (b) Translocation of GLUT4 increased in gastrocnemius muscle and (c) reduction in muscle glycogen levels. Objective: In the face of these findings, the present study aims to elucidate the mitochondrial energy metabolism and its relation to the epileptic crises induced by sound stimuli. Results: Through behavioral analysis and indirect calorimetry, we report that WAR has reduced exploratory activity and has preference to oxidize amino acids; Using biopsies of liver tissue, skeletal and cardiac muscles, we observe greater mitochondrial density, accompanied by greater generation of H2O2 and as a result of greater oxidative stress; in the search to elucidate with greater dexterity, we perform isolation of the mitochondrial fraction of the hepatic tissue, and we conclude that there is no greater generation of H2O2 by mitochondria, but there is a protein enrichment (some functional proteins - such as those involved in OXPHOS - and other nonfunctional ones - such as UCPs), in addition to reporting higher levels of proteins involved in mitochondrial dynamics, so we can conclude that WAR has greater mitochondrial density and mitochondria more efficiently; the same mitochondrial profile was observed in the brain tissue. After treatment with DNP and NAC, we observed reduction of oxidative stress in the brain tissue, but only NAC reduced the severity of the crisis, so we conclude that the smooth decoupling induced by DNP is not able to significantly reduce the severity of the crisis, however the inhibition of glycolysis by the NAC, altered the brain bioenergetics is able to reduce the severity of the crisis, leaving evidence that the energy metabolism has essential/relevant role in the epileptic crisis induced by sound stimuli in WAR, while oxidative stress has secondary role.

O presente trabalho descreve o uso de eletrodos de carbono vítreo como eletrodo-base para modificação com hexacianoferratos de Fe (FeHCF), Co (CoHCF) e Ni (NiHCF) por meio da adsorção destes complexos utilizando a técnica de voltametria cíclica. Os eletrodos quimicamente modificados (EQMs) preparados por este método apresentam características diferenciadas tais como robustez e estabilidade ao longo das medidas eletroquímicas, além de boas propriedades redox. Os EQMs com FeHCF e NiHCF foram avaliados em função da sua atividade eletrocatalítica para a reação de oxidação do Ácido Ascórbico em solução de KCl 0,1 mol L-1 (pH 6,6). O EQM com CoHCF foi avaliado nas mesmas condições dos outros filmes, porém não apresentou uma diminuição no sobrepotencial de oxidação do Ácido Ascórbico. Embora não tenha apresentado uma resposta semelhante aos EQMs com FeHCF e NiHCF, o EQM com CoHCF apresentou a melhor sensibilidade da resposta de corrente de pico quando comparado aos demais. A fim de proporcionar a renovação da superfície do eletrodo foi avaliada a utilização de eletrodos de pasta de carbono modificada com FeHCF, CoHCF ou NiHCF. Os parâmetros de composição da pasta, o eletrólito suporte e o pH foram avaliados utilizando o EPCM com FeHCF por meio da técnica de voltametria cíclica e os parâmetros otimizados foram aplicados no uso dos EPCM com CoHCF e NiHCF. Para avaliar a sensibilidade na deteccção da L-Cisteína, do Glifosato e da N-Acetilcisteína, os EPCMs modificados foram submetidos a estudos com a técnica de voltametria de onda quadrada. Todos os analitos apresentaram resposta eletroquímica em todos os EPCMs, porém as melhores respostas foram para o FeHCF na presença de L-Cisteína, CoHCF na presença de Glifosato e NiHCF na presença de N-Acetilcisteína. Na presença de 1 x 10-8 mol L-1 dos analitos os EPCMs com hexacianoferratos apresentaram um boa resposta eletroquímica, embora não tenha sido possível observar uma linearidade entre o aumento da concentração dos analitos propostos e a corrente de pico. Essa sensibilidade demonstrada pelos EPCMs na presença de moléculas com grupos funcionais, como ácidos carboxílicos, aminoácidos e tióis abre novas perspectivas para a análise direta de compostos de interesse clínico, farmacêutico e amostras de interesse ambiental. / This work describes the use of glassy carbon electrodes as the base for electrode modification with hexacyanoferrates of Fe (FeHCF), Co (CoHCF) and Ni (NiHCF) through adsorption of these complexes using cyclic voltammetry. The chemically modified electrodes (CMEs) prepared by this method have specific features such as robustness and stability along the electrochemical measurements, and good redox properties. The CME with FeHCF and NiHCF were evaluated take into accounting their electrocatalytic activity for oxidation reaction of Ascorbic Acid in KCl 0.1 mol L-1 (pH 6.6). The CME with CoHCF was evaluated under the same conditions, but did not show a decrease on the overpotential for Ascorbic Acid oxidation. Although the CME with CoHCF has not showed the same behavior presented by CMEs with FeHCF and NiHCF, the CME with CoHCF presented the best sensitivity in order to relationship between peak current and concentration of Ascorbic Acid when compared to CMEs with either. In order to provide the renewal of the electrode surface was evaluated the use of carbon paste electrodes (CPEs) modified with FeHCF, CoHCF and NiHCF. The CPE parameters such as composition, supporting electrolyte and pH were evaluated using the CPE with FeHCF by cyclic voltammetry and these optimized parameters were applied for CPEs with CoHCF and NiHCF. The studies about the sensitivity of the detection for L-Cysteine, glyphosate and N-acetylcysteine using the modified CPEs with hexacyanoferrates were performed by square wave voltammetry. All analytes showed electrochemical response at all CPEs, but the best electrochemical responses were obtained for FeHCF in the presence of L-Cysteine, CoHCF in the presence of glyphosate and NiHCF in the presence of N-acetylcysteine. The CPEs with hexacyanoferrates in the presence of 1 x 10-8 mol L-1 of L-Cysteine, glyphosate or N-acetylcysteine had showed a good electrochemical response, although were not possible to observe a linear correlation between the concentration of analytes and peak current. This sensitivity demonstrated by CPEs with hexacyanoferrates electrodes in presence of specific functional groups such as carboxylic acids, amino acids and thiols opens new perspectives for the direct analysis of compounds with clinical, pharmaceutical and environmental samples.

Störungen im Bereich der Mikrozirkulation gelten als ursächlich für die Entstehung des Multiorganversagens bei Sepsis, wobei der Darm eine zentrale Rolle einnimmt. Aktivierte Leukozyten setzen u.a. Sauerstoffradikale frei, die entscheidend zur Zerstörung der endothelialen Integrität beitragen. Die Antagonisierung schädigender Mediatoren stellt ein Prinzip der adjunktiven Sepsis-Therapie dar, wobei die antioxidativ wirkenden Substanzen N-Acetylcystein (NAC) und Tirilazad Mesylat (TM) in mehreren Studien positive Effekte gezeigt haben. In einer tierexperimentellen Untersuchung an Ratten wurde der Effekt der kombinierten Gabe von NAC und TM auf die mesenteriale Mikrozirkulation, auf die Freisetzung von TNF-alpha, IL-1beta, IL-6, IL-10 und auf die Leukozytenzahl unter einer kontinuierlichen Lipopolysaccharidbelastung (LPS) von 10 mg/kg KG untersucht. Die Beurteilung der mesenterialen Mikrozirkulation erfolgte mittels Intravitalmikroskopie. Hierbei wurde das Ausmaß der Leukozytenadhärenz am Endothel der mesenterialen Venolen als Maß für die Leukozytenaktivierung und die Plasmaextravasation als Parameter für die Endotheldysfunktion bestimmt. Dabei konnte während zwei Stunden Endotoxinämie die Zunahme der Plasmaextravasation an mesenterialen Venolen durch die kombinierte Gabe von NAC und TM nicht signifikant beeinflusst werden (p>0,05). Eine tendenziell erhöhte Plasmaextravasation unterstützt die Hypothese, dass leukozytenunabhängige Mechanismen für die Plasmaextravasation existieren. Während zwei Stunden Endotoxinämie kam es zu einer signifikanten Reduktion der Anzahl der fest adhärenten Leukozyten in der NAC/TM-Gruppe im Vergleich zur LPS-Gruppe (p=0,001). Durch die kombinierte Gabe von NAC und TM konnte die endotoxininduzierte Freisetzung von TNF-alpha, IL-1beta, IL-6, IL-10 und die endotoxinbedingte Leukopenie nicht signifikant beeinflusst werden. / Disturbances of the microcirculation are causal for the pathophysiology of multiorgan failure related to sepsis in which the gut plays a central part. Activated leukocytes release i.e. oxygen radicals which decisively contribute to the destruction of the endothelial integration. To antagonize the damaging mediators is a principle of the adjunctive sepsis therapy in which the antioxidant agents N-acetylcysteine (NAC) and tirilazad mesylate (TM) showed positive effects in several studies. The effect of the combined administering of NAC and TM under continuous lipopolysaccharide (LPS) exposure of 10 mg/kg BW on the mesenteric microcirculation, on the release of TNF-alpha, IL-1beta, IL-6, IL-10 and on the number of leukocytes was examined in an animal study on rats. The appraisal of the microcirculation was done by intravital microscopy. The degree of leukocyte adherence on the endothelium of mesenteric venules was determined for the degree of leukocyte activation, and the plasma extravasation was the parameter for the endothelial dysfunction. The increase of plasma extravasation on mesenteric venules during 2 hours of endotoxemia could not be affected significantly by the combined administering of NAC and TM. The tendency of increased plasma extravasation supports the hypothesis of the existence of a leukocyte independent mechanism of plasma extravasation. During 2 hours of endotoxemia the NAC/TM group showed a significant decrease in the number of firmly adherent leukocytes in comparison to the LPS group. There was no significant effect on the endotoxin induced release of TNF-alpha, IL-1beta, IL-6, IL-10 and the endotoxin induced leukopenia by the combined administration of NAC and TM.

Introdução: Já foi mostrado que o óxido nítrico (NO) age como um potente inibidor da peroxidação lipídica, um dos principais contribuintes para a fibrogênese na esteatohepatite não-alcoólica (EHNA). O S-Nitroso-N-acetilcisteína (SNAC), um doador de NO, modula a ativação de células estreladas hepáticas e tem mostrado efeitos benéficos na EHNA experimental. O objetivo deste estudo foi avaliar a eficácia do SNAC como um agente anti-fibrogênico na EHNA experimental. Métodos: Ratos Sprague-Dawley adultos foram alimentados com dieta hiperlipídica deficiente em colina e expostos a dietilnitrosamina (DEN) durante 8 semanas. Dez animais receberam SNAC (1,4 mg/ kg) por gavagem diariamente (grupo SNAC) e 10 receberam veículo (grupo EHNA). Três animais receberam somente dieta padrão e veículo (grupo Controle). Após este período, os animais foram sacrificados e o tecido hepático retirado para avaliação histológica, quantificação do colágeno e análises de expressão gênica. Genes relacionados à fibrose [metaloproteinase de matriz (MMP)- 2, 9 e 13, e, TGF b -1, colágeno-1a, inibidor tecidual de metaloproteinase (TIMP)-1 e 2] e genes relacionados ao estresse oxidativo [proteínas de choque térmico (HSP)-60 e 90] foram avaliados. Resultados: O SNAC levou a atenuação da fibrose hepática verificada pela quantificação de colágeno, e este efeito foi associado com supra-regulação da MMP- 13, MMP-9 e infra-regulação da HSP-60, TIMP-2, TGF b -1 e colágeno-1a. Conclusões: O SNAC apresenta propriedades anti-fibrogênicas no modelo de EHNA empregado, infra-regula moléculas pró-fibrogênicas e supra-regula a MMP-13, um fator determinante da degradação do colágeno intersticial. Nossa hipótese é que o SNAC, pela redução do estresse oxidativo, leva a um padrão de expressão gênica que favorece uma maior remoção de colágeno, com conseqüente atenuação da fibrose hepática na EHNA, sugerindo que SNAC é um potencial agente anti-fibrogênico neste contexto / Introduction: Nitric oxide (NO) has already been shown to act as a potent inhibitor of lipid peroxidation, a major contributor for fibrogenesis in nonalcoholic steatohepatitis (NASH). S-Nitroso-N-acetylcysteine (SNAC), an NO donor, modulates hepatic stellate cells activation and has shown beneficial effects on experimental NASH. The aim of this study was to evaluate the effectiveness of SNAC as an antifibrogenic agent in experimental NASH. Methods: Adult Sprague-Dawley rats were fed choline-deficient high fat diet and exposed to diethylnitrosamine during 8 weeks, during which 10 animals received SNAC (1.4 mg/kg) by daily gavage (SNAC group) and 10 animals received vehicle (NASH group). Another group (Control; n=3) received only standard diet and vehicle. After this period, liver tissue was obtained for histological study, collagen quantification and gene expression analyses. Genes related to fibrosis [matrix metalloproteinase (MMP)-13, 9 and 2, TGFb-1, collagen-1a, tissue inhibitor of metalloproteinase (TIMP)-1 and 2] and genes related to oxidative stress [heat-shock protein (HSP)-60 and 90] were evaluated. Results: SNAC led to attenuation of liver fibrosis, verified through collagen quantification, and this effect was associated with up-regulation of MMP-13, MMP-9 and down-regulation of HSP-60, TIMP-2, TGFb-1 and collagen-1a. Conclusions: SNAC shows antifibrogenic properties in the NASH model employed, down-regulates profibrogenic molecules and up-regulates MMP-13, a key determinant of interstitial collagen degradation. We hypothesize that SNAC, through oxidative stress lowering, leads to a gene expression pattern that favors greater collagen removal, with consequent attenuation of liver fibrosis in NASH. Our findings suggest that SNAC is a potential antifibrogenic agent in this setting

Extended periods of oxygen deprivation cause brain death in mammals but the western painted turtle overwinters in anoxic mud for months without damage. Neural protection is achieved through decreases in the whole cell currents of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) that are dependent on a mild increase in intracellular calcium from the mitochondria. The goal of this research was to determine if natural anoxic decreases in reactive oxidative species (ROS) serve as the signal to bring about these changes. Reductions in cellular ROS levels were demonstrated to have no effect on AMPAR currents or intracellular calcium and produced massive increases in NMDAR currents, indicating that ROS depression does not directly mediate anoxic alterations. Interestingly, mammalian neural tissue also experiences a similar increase in NMDAR whole cell current in response to reducing agents suggesting a possible conserved mechanism for normoxic receptor control.

Objectifs Aucun agent n’a été approuvé pour prévenir l’ototoxicité secondaire au cisplatin. Nos objectifs consistaient à évaluer la protection auditive offerte par le lactate et le N-acétylcystéine (NAC) intra-tympaniques après injection de cisplatin, ainsi que l’absorption systémique du NAC intra-tympanique. Méthodes Seize cochons d’inde formaient 2 groupes ayant reçu une solution de lactate et de NAC à 20% dans l’oreille testée. L’oreille contro-latérale a reçu une solution saline contrôle. Après 30 minutes, une injection intrapéritonéale de 3 mg/kg de cisplatin a été effectuée et répétée une fois par semaine jusqu’à une dose finale de 24 mg/kg. Les potentiels évoqués auditifs du tronc cérébral (PEATC) ont été mesurés avant les injections, après 9 mg/kg et 24 mg/kg de cisplatin. Les cochlées ont été analysées au microscope électronique à balayage. La diffusion systémique du NAC a été évaluée par chromatographie en phase liquide. Résultats Pour les oreilles contrôles, les seuils auditifs des PEATC ont augmenté uniformément sur toutes les fréquences (28,4 dB en moyenne). Le groupe lactate montrait une augmentation moins importante (17,0 dB). Les basses fréquences étaient nettement moins affectées. Le groupe NAC a subi une augmentation des seuils de 89 dB. La microscopie électronique a démontré une préservation partielle des cellules ciliées externes des cochlées traitées au lactate et une destruction complète de celles traitées au NAC. La chromatographie n’a démontré aucune diffusion de NAC. Conclusions Le lactate offre une protection partielle significative contre l’ototoxicité induite par le cisplatin. Les injections de NAC n’offrent pas de protection lorsque administrées en concentrations élevée. Le NAC intra-tympanique ne se diffuse pas systémiquement. / Objectives There is no approved agent to prevent cisplatin-induced ototoxicity. Our objectives are to identify and compare the protective effect of intratympanic injections of lactate or N-acetylcysteine (NAC) in the prevention of cisplatin-induced ototoxicity and to study systemic diffusion of intratympanic NAC. Methods Sixteen guinea pigs, forming two groups, received respectively intratympanic lactate and 20% NAC in one ear. The contra-lateral ears received a control saline solution. After 30 minutes, an intra-peritoneal cisplatin injection of 3 mg/kg was performed and repeated once a week to achieve a final dose of 24mg/kg. Auditory brainstem responses (ABR) were recorded before any injection, after 9mg/kg and after 24mg/kg of cisplatin for the frequencies 2, 4, 6 and 8kHz. Cochleas were analyzed under scanning electron microscope. Systemic diffusion of NAC was studied using high performance liquid chromatography. Results For the control ears, ABR thresholds increased uniformly by an average of 28.4dB. The lactate group showed a lower threshold increase by an average of 17.0dB. The NAC showed an important threshold increase of 89.0dB. Lactate showed a significant hearing protection at 2000Hz (p<0.01). Electron microscopy revealed partial preservation of cochlear outer hair cells stereocilia for the ears treated with lactate and severe disruption for NAC group. No systemic diffusion of NAC was observed with chromatography. Conclusion Lactate offers significant partial protection against cisplatin-induced ototoxicity. NAC does not offer any protection when administered in high concentrations. Intratympanic NAC does not diffuse systemically.

Extended periods of oxygen deprivation cause brain death in mammals but the western painted turtle overwinters in anoxic mud for months without damage. Neural protection is achieved through decreases in the whole cell currents of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) that are dependent on a mild increase in intracellular calcium from the mitochondria. The goal of this research was to determine if natural anoxic decreases in reactive oxidative species (ROS) serve as the signal to bring about these changes. Reductions in cellular ROS levels were demonstrated to have no effect on AMPAR currents or intracellular calcium and produced massive increases in NMDAR currents, indicating that ROS depression does not directly mediate anoxic alterations. Interestingly, mammalian neural tissue also experiences a similar increase in NMDAR whole cell current in response to reducing agents suggesting a possible conserved mechanism for normoxic receptor control.