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OBJECTIVE: Aqueous extract of Anacyclus pyrethrum (AEAPR) is used in traditional medicine to treat epilepsy, but whether it has antiseizure properties has not been established. Because extracts of the plant have antioxidant properties, we hypothesized that it may be particularly potent in conditions associated with oxidative stress, in particular social isolation. METHODS: We addressed these objectives in the pilocarpine experimental model of epilepsy using socially isolated rats maintaining contacts with (handled) and without (unhandled) positive handling strategy. Both groups were further divided into treated (AEAPR was added to the drinking water) and untreated groups. Continuous (24/7) electroencephalography (EEG) recordings started in the sixth week after status epilepticus (SE) with a predrug control period of 3 weeks, followed by 3 weeks of daily treatment with AEAPR or water, and finally a postdrug control period of 3 weeks. At the end of the experimental procedure, we measured lipid peroxidation, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities in the hippocampus to assess oxidative stress. RESULTS: A. pyrethrum treatment significantly reduced seizure frequency by 51% and 57%, duration by 30% and 33%, and severity by 31% and 26% in isolated handled and unhandled rats, respectively. The beneficial effects on seizures were still present 3 weeks after the end of the treatment. The treatment reduced lipid peroxidation as well as SOD, GPx, and catalase activities. SIGNIFICANCE: We conclude that A. pyrethrum has antiseizure and antioxidant properties, even in social isolation conditions.
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Chrysanthemum cinerariifolium , Epilepsia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Catalase/metabolismo , Chrysanthemum cinerariifolium/metabolismo , Epilepsia/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Convulsões , Superóxido Dismutase/metabolismoRESUMO
Major depressive disorder (MDD) in children and adolescents is a recurrent and disabling condition globally but its pathophysiology remains poorly elucidated and there are limited effective treatments available. We performed metabolic profiling of plasma samples based on ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry to explore the potential biomarkers of depression in children and adolescents with MDD. We identified several perturbed pathways, including fatty acid metabolism-particularly the polyunsaturated fatty acids metabolism, and purine metabolism-that were associated with MDD in these young patients. In addition, inosine was shown as a potential independent diagnostic biomarker for MDD, achieving an area under the ROC curve of 0.999 in discriminating drug-naive MDD patients and 0.866 in discriminating drug-treated MDD from healthy controls. Moreover, we found evidence for differences in the pathophysiology of MDD in children and adolescents to that of adult MDD, specifically with tryptophan metabolism. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and the pathophysiology and diagnostic biomarker of child and adolescent MDD.
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Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Adolescente , Biomarcadores , Estudos de Casos e Controles , Criança , China , Cromatografia Líquida de Alta Pressão , Depressão/diagnóstico , Depressão/metabolismo , Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/metabolismo , Feminino , Humanos , Inosina/metabolismo , Metabolismo dos Lipídeos , Masculino , Espectrometria de Massas , Metabolômica/métodos , Purinas/metabolismo , Curva ROC , Triptofano/metabolismoRESUMO
OBJECTIVE: Unresolved past stressful events can induce a state of vulnerability to epilepsy and comorbidities. Using an experimental model of stress-induced vulnerability to depression, we tested whether an antioxidant treatment applied after the onset of epileptogenesis was disease modifying and could prevent the occurrence of comorbidities. METHODS: We used social defeat (SD) to trigger a state of vulnerability in half of the SD-exposed population of rats. One month after SD, we used repeated injections of kainic acid to trigger status epilepticus (SE). One subset of animals was treated after SE during 2 weeks with Tempol, a strong antioxidant. Supradural 24/7 recordings were used to assess the development of epilepsy. We assessed spatial and nonspatial memory as well as a depressionlike profile 6 weeks after SE. RESULTS: Serum brain-derived neurotrophic factor (BDNF) levels decreased after SD in all animals and recovered to pre-SD levels 1 month later in half of them (SDN group). The other half kept low serum BDNF levels (SDL group). At that stage, SDN and SDL animals do not present a depressionlike profile. The SDL group was more sensitive than the SDN group to epileptogenic conditions. Following SE, the SDL group displayed accelerated epileptogenesis, a depressionlike profile, and severe cognitive deficits as compared to SDN rats. Transient Tempol treatment was disease-modifying, reducing the number of seizures, and prevented the development of comorbidities in the SDL group. Tempol treatment normalized oxidative stress in the SDL group to SDN levels. SIGNIFICANCE: This study illustrates the disease-modifying effect of antioxidant treatment after the onset of epileptogenesis in a population rendered vulnerable by past stressful events. The transient treatment decreased seizure burden and had long-term effects, preventing the occurrence of a depressionlike profile and cognitive deficits. We propose that vulnerability to comorbidities can be reversed after the onset of epilepsy.
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Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Epilepsia/psicologia , Angústia Psicológica , Estado Epiléptico/psicologia , Animais , Comorbidade , Convulsivantes/toxicidade , Óxidos N-Cíclicos/farmacologia , Epilepsia/induzido quimicamente , Ácido Caínico/toxicidade , Ratos , Marcadores de Spin , Estado Epiléptico/induzido quimicamenteRESUMO
Repeated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for 4 consecutive days. Respiratory rate was recorded under anesthesia 6 days (D+10) or 26 days (D+30) after social defeat. At D+10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike nondefeated animals. At D+30, all signs of anxiety had disappeared. However, one-half of the rats still displayed bradypnea (DL rats, for low respiratory rate indicated by a lower RSA frequency), whereas those with higher respiratory rate (DH rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT3 receptors reversed bradypnea in all D rats at D+10 and in DL rats at D+30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between D+10 and D+18, whereas DL rats remained bradypneic until D+30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until D+10, followed by recovery. However, bradypnea may persist in one-half of the population up until D+30, despite apparent recovery of the anxiety-like state.
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Ansiedade/fisiopatologia , Comportamento Animal , Hipoventilação/fisiopatologia , Taxa Respiratória , Comportamento Social , Estresse Psicológico , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Accumulation of stressful events can render individuals susceptible to develop epilepsy and comorbidities. Whether such vulnerability can be predicted and reversed is not known. Here we show that social defeat, although not producing depression by itself, produced in 50% of rats reduced threshold for status epilepticus (SE), accelerated epileptogenesis, and once epilepsy was induced, depression-like profile and cognitive deficits. Low serum brain-derived neurotrophic factor (BDNF) levels measured before SE identified this vulnerable population. Treatment with a BDNF analog before SE prevented the occurrence of comorbidities. Thus, vulnerability to comorbidities after epilepsy onset due to unresolved past stressful events may be predicted and reversed.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Depressão/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Meio Social , Estado Epiléptico/metabolismo , Estresse Psicológico/metabolismo , Alostase , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/psicologia , Depressão/psicologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Epilepsia/psicologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Flavonas/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ácido Caínico/toxicidade , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estresse Psicológico/psicologiaRESUMO
Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders.
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Ansiedade/fisiopatologia , Hipotálamo/fisiologia , Núcleo Solitário/fisiologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Animais , Barorreflexo/fisiologia , Comportamento Animal , Pressão Sanguínea , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Núcleo Hipotalâmico Dorsomedial/fisiologia , Granisetron/farmacologia , Frequência Cardíaca , Masculino , Muscimol/farmacologia , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Receptores 5-HT3 de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologiaRESUMO
Stress can push individuals close to the threshold to depression. An individual's intrinsic vulnerability before a stressful event determines how close they come to the threshold of depression. Identification of vulnerability biomarkers at early (before the stressful event) and late (close to the threshold after the stressful event) stages would allow for corrective actions. Social defeat is a stressful event that triggers vulnerability to depression in half of exposed rats. We analyzed the sleep properties of rats before (baseline) and after (recovery) social defeat by telemetry electroencephalogram recordings. Using Gaussian partitioning, we identified three non-rapid eye movement stages (N-S1, N-S2, and N-S3) in rats based on a sleep depth index (relative δ power) and a cortical activity index (fractal dimension). We found (1) that, at baseline, N-S3 lability and high-θ relative power in wake identified, with 82% accuracy, the population of rats that will become vulnerable to depression after social defeat, and (2) that, at recovery, N-S1 instability identified vulnerable rats with 83% accuracy. Thus, our study identified early and late sleep biomarkers of vulnerability to depression, opening the way to the development of treatments at a prodromal stage for high sensitivity to stress, and for stress-induced vulnerability to depression.
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Depressão , Sono , Ratos , Animais , Depressão/etiologia , Eletroencefalografia , Biomarcadores , Fases do SonoRESUMO
Stress has been identified as a major contributor to human disease and is postulated to play a substantial role in epileptogenesis. In a significant proportion of individuals with epilepsy, sensitivity to stressful events contributes to dynamic symptomatic burden, notably seizure occurrence and frequency, and presence and severity of psychiatric comorbidities [anxiety, depression, posttraumatic stress disorder (PTSD)]. Here, we review this complex relationship between stress and epilepsy using clinical data and highlight key neurobiological mechanisms including the hypothalamic-pituitary-adrenal (HPA) axis dysfunction, altered neuroplasticity within limbic system structures, and alterations in neurochemical pathways such as brain-derived neurotrophic factor (BNDF) linking epilepsy and stress. We discuss current clinical management approaches of stress that help optimize seizure control and prevention, as well as psychiatric comorbidities associated with epilepsy. We propose that various shared mechanisms of stress and epilepsy present multiple avenues for the development of new symptomatic and preventative treatments, including disease modifying therapies aimed at reducing epileptogenesis. This would require close collaborations between clinicians and basic scientists to integrate data across multiple scales, from genetics to systems biology, from clinical observations to fundamental mechanistic insights. In future, advances in machine learning approaches and neuromodulation strategies will enable personalized and targeted interventions to manage and ultimately treat stress-related epileptogenesis.
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Epilepsia , Transtornos de Estresse Pós-Traumáticos , Humanos , Epilepsia/terapia , Epilepsia/complicações , Convulsões/complicações , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Ansiedade , AnsiedadeRESUMO
BACKGROUND: Several studies implicate brain-derived neurotrophic factor (BDNF) in the pathophysiology of epilepsy. In particular, preclinical data suggest that lower serum BDNF is a biomarker of epilepsy severity and psychiatric comorbidities. We tested this prediction in clinical epilepsy cohorts. METHODS: Patients with epilepsy were recruited from 4 epilepsy centers in France and serum BDNF was quantified. Clinical characteristics including epilepsy duration, classification, localization, etiology, seizure frequency and drug resistance were documented. Presence of individual anti-seizure medications (ASM) was noted. Screening for depression and anxiety symptoms was carried out in all patients using the NDDI-E and the GAD-7 scales. In patients with positive screening for anxiety and/or depression, detailed psychiatric testing was performed including the Mini International Neuropsychiatric Interview (MINI), STAI-Y, Holmes Rahe Stressful Events Scale and Beck Depression Interview. Descriptive analysis was applied. Spearman's test and Pearson's co-efficient were used to assess the association between BDNF level and continuous variables. For discrete variables, comparison of means (Student's t-test, Mann-Whitney u-test) was used to compare mean BDNF serum level between groups. Multivariate analysis was performed using a regression model. RESULTS: No significant correlation was found between serum BDNF level and clinical features of epilepsy or measures of depression. The main group-level finding was that presence of any ASM at was associated with increased BDNF; this effect was particularly significant for valproate and perampanel. CONCLUSION: Presence of ASM affects serum BDNF levels in patients with epilepsy. Future studies exploring BDNF as a possible biomarker of epilepsy severity and/or psychiatric comorbidity must control for ASM effects.
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Fator Neurotrófico Derivado do Encéfalo , Epilepsia , Humanos , Comorbidade , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Ansiedade , Escalas de Graduação Psiquiátrica , Biomarcadores , Depressão/diagnóstico , Depressão/epidemiologiaRESUMO
A stressful event increases the risk of developing depression later in life, but the possible predisposing factors remain unknown. Our study aims to characterize latent vulnerability traits underlying the development of depressive disorders in adult animals. Four weeks after a priming stressful event, serum corticosterone concentration returned to control values in all animals, whereas the other biological parameters returned to basal level in only 58% of animals (called nonvulnerable). In contrast, 42% of animals displayed persistent decreased serum and hippocampus BDNF concentrations, reduced hippocampal volume and neurogenesis, CA3 dendritic retraction and decrease in spine density, as well as amygdala neuron hypertrophy, constituting latent vulnerability traits to depression. In this group, called vulnerable, a subsequent mild stress evoked a rise of serum corticosterone levels and a "depressive" phenotype, in contrast to nonvulnerable animals. Intracerebroventricular administration of 7,8-dihydroxyflavone, a selective TrkB receptor agonist, dampened the development of the "depressive" phenotype. Our results thus characterize the presence of latent vulnerability traits that underlie the emergence of depression and identify the association of low BDNF with normal corticosterone serum concentrations as a predictive biomarker of vulnerability to depression.
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Biomarcadores/metabolismo , Encéfalo/fisiologia , Transtorno Depressivo/patologia , Plasticidade Neuronal/fisiologia , Animais , Antidepressivos Tricíclicos/farmacologia , Biomarcadores/análise , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células , Comportamento Competitivo , Corticosterona/sangue , Transtorno Depressivo/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Imipramina/farmacologia , Estudos Longitudinais , Masculino , Neurônios/patologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Meio Social , Estresse Psicológico/metabolismo , Natação/psicologia , Paladar/fisiologiaRESUMO
Defence responses triggered experimentally in rats by stimulation of the dorsomedial nucleus of the hypothalamus (DMH) and the dorsolateral periaqueductal grey matter (PAG) inhibit the cardiac baroreflex response (i.e. bradycardia). It has also been proposed that the midbrain cuneiform nucleus (CnF) is involved in active responses. Our aim was to identify the neurocircuitry involved in defence-induced baroreflex inhibition, with a particular focus on the link between DMH, CnF and dorsolateral PAG. Microinjection of the anterograde tracer Phaseolus vulgaris leucoaggutinin into the CnF revealed a dense projection to the dorsolateral PAG. Moreover, activation of neurons in the CnF induced increased expression of Fos protein in the dorsolateral PAG. Inhibition of neurons of the CnF or dorsolateral PAG prevented the inhibition of baroreflex bradycardia induced by DMH or CnF stimulation, respectively. These results provide a detailed description of the brain circuitry underlying acute baroreflex modulation by neurons of the DMH. Our data have shown for the first time that the CnF plays a key role in defence reaction-associated cardiovascular changes; its stimulation, from the DMH, activates the dorsolateral PAG, which, in turn, inhibits baroreflex bradycardia.
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Barorreflexo , Bradicardia/prevenção & controle , Frequência Cardíaca , Mesencéfalo/fisiopatologia , Inibição Neural , Vias Neurais/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Análise de Variância , Animais , Barorreflexo/efeitos dos fármacos , Bradicardia/metabolismo , Bradicardia/fisiopatologia , Fármacos Cardiovasculares/administração & dosagem , Mecanismos de Defesa , Retroalimentação Fisiológica , Frequência Cardíaca/efeitos dos fármacos , Masculino , Núcleo Mediodorsal do Tálamo/fisiopatologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Microinjeções , Inibição Neural/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Técnicas de Rastreamento Neuroanatômico , Marcadores do Trato Nervoso/administração & dosagem , Neurotransmissores/administração & dosagem , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Fito-Hemaglutininas/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Stress reactivity is a complex phenomenon associated with multiple and multimodal expressions and functions. Herein, we hypothesized that compared with healthy controls (HCs), adolescents with borderline personality disorder (BPD) would exhibit a stronger response to stressors and a deficit in self-perception of stress due to their lack of insight. Twenty adolescents with BPD and 20 matched HCs performed a socially evaluated mental arithmetic test to induce stress. We assessed self- and heteroperception using both human ratings and affective computing-based methods for the automatic extraction of 39 behavioral features (2D + 3D video recording) and 62 physiological features (Nexus-10 recording). Predictions were made using machine learning. In addition, salivary cortisol was measured. Human ratings showed that adolescents with BPD experienced more stress than HCs. Human ratings and automated machine learning indicated opposite results regarding self- and heteroperceived stress in adolescents with BPD compared to HCs. Adolescents with BPD had higher levels of heteroperceived stress than self-perceived stress. Similarly, affective computing achieved better classification for heteroperceived stress. HCs had an opposite profile; they had higher levels of self-perceived stress, and affective computing reached a better classification for self-perceived stress. We conclude that adolescents with BPD are more sensitive to stress and show a lack of self-perception (or insight). In terms of clinical implications, our affective computing measures may help distinguish hetero- vs. self-perceptions of stress in natural settings and may offer external feedback during therapeutic interaction.
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Transtorno da Personalidade Borderline/psicologia , Autoimagem , Estresse Psicológico/psicologia , Adolescente , Feminino , Humanos , Hidrocortisona/análise , Aprendizado de Máquina , Masculino , MatemáticaRESUMO
(1) Background: While a number of studies among military personnel focus on specific pathologies such as post-traumatic stress disorder (PTSD), anxiety, and depression, they do not address the cumulative impact on mental health of stressors related to the profession. The present study aims to determine the relationship between allostatic load and mental health status in a cohort of fit-for-duty soldiers prior to their deployment to Afghanistan. The aim is to better-define the consequences of stressor adjustment. (2) Methods: A cohort of 290 soldiers was evaluated in a cross-sectional study with respect to psychopathology (PTSD, anxiety, depression), psychological functioning (stress reactivity, psychological suffering), and allostatic profile (urinary cortisol and 8-iso-PGF2α, blood cortisol and BDNF). A hierarchical cluster analysis was used to identify allostatic patterns. (3) Results: Around 10% of the cohort reported high scores for psychopathology, and biological alterations were identified. For the remainder, four allostatic profiles could be identified by their psychological functioning. (4) Conclusions: Both biological and psychological assessments are needed to characterize subthreshold symptomatology among military personnel. The psychological significance of allostatic load should be considered as a way to improve health outcomes.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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After social stress, rats become vulnerable to depression, and this state is characterized by persistent low blood levels of brain-derived neurotrophic factor (BDNF). The aim of this study was to determine whether low BDNF levels are associated with long term autonomic changes. Defeated animals were subjected to four daily episodes of social defeats. Twenty five days later, defeated rats with low BDNF levels (Dlow) still displayed elevated sympathetic tone (as indicated by an elevated low frequency to high frequency ratio (LF/HF) in heart rate) and elevated blood pressure, as well as reduced baroreflex sensitivity (BRS). In contrast, those with higher BDNF levels (Dhigh) similar to controls, did not. Dlow animals persistent cardiovascular changes were abolished by acute inhibition of the dorsomedial nucleus of the hypothalamus (DMH). These cardiovascular changes were also prevented by chronic sub-cutaneous osmotic infusion of losartan, an angiotensin II type 1 receptor (AT1) receptor antagonist, started immediately after social defeat. In conclusion, the results show that greater vulnerability to stress consequences following a traumatic event is associated with an elevated LF/HF ratio, a persistent high blood pressure and a low BRS, all due to an AT1 receptor activation.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sistema Cardiovascular/metabolismo , Relações Interpessoais , Receptor Tipo 1 de Angiotensina/metabolismo , Estresse Psicológico/metabolismo , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Suscetibilidade a Doenças , Frequência Cardíaca/efeitos dos fármacos , Losartan/farmacologia , Masculino , Osmose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologiaRESUMO
Recent trials of chronic EEG in humans showed that epilepsy is a cyclical disorder of the brain with rhythms at multiple time-scales: circadian, multi-day (multidien) or even seasonal. Here, we analyzed chronic EEG data (>30â¯days) in male epileptic rats and unraveled not only circadian but also, slower, multidien rhythms of interictal epileptiform activity with periodicity of about 2-3 and 5-7â¯days. Importantly, seizures were not uniformly distributed over time, but rather clustered at preferential phases of these underlying rhythms, delineating critical circadian times and multidien phase of heightened seizure risk. Multidien rhythms were not synchronous across animals or with human intervention suggesting an endogenous generator. In epilepsy, across species, unknown factors modulate seizure timing in cyclical patterns over multiple days.
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Epilepsia do Lobo Temporal/fisiopatologia , Periodicidade , Animais , Ritmo Circadiano , Eletroencefalografia , Meio Ambiente , Masculino , Ratos , Ratos Sprague-Dawley , Convulsões/fisiopatologiaRESUMO
Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor κB (NF-κB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-κB is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-κB pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-κB super- repressor IκBα resulted in an inhibition of the NF-κB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IκBα overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-κB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-κB pathway in the development of neuropathic pain after peripheral nerve injury.
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BACKGROUND: Aldosterone, the final mediator of the renin-angiotensin-aldosterone pathway, is at its highest plasma levels at presentation for ST-elevation myocardial infarction (STEMI). Whether aldosterone level at presentation for STEMI is associated with adverse outcome remains unknown. METHODS AND RESULTS: Plasma aldosterone levels were measured at presentation in consecutive patients referred for primary percutaneous coronary intervention for STEMI. We assessed the association between aldosterone levels and in-hospital events and mortality during a 6-month follow-up. Of 356 STEMI patients, 23 and 36 died during the hospital stay and 6-month follow-up period, respectively. Nine other patients survived in-hospital cardiac arrest. High aldosterone levels were associated with an almost stepwise increase in rates of in-hospital death (P=0.01), cardiovascular death (P=0.03), heart failure (P=0.005), ventricular fibrillation (P=0.02), and resuscitated cardiac arrest (P=0.01). After adjustment for age, Killip class, and reperfusion status, compared with patients in the first aldosterone quartile group, those in the highest quartile were at higher risk of death (hazard ratio 3.28, 95% CI 1.09 to 9.89, P=0.035) and death or resuscitated cardiac arrest (hazard ratio 3.74, 95% CI 1.40 to 9.98, P=0.008) during the follow-up. CONCLUSIONS: Plasma aldosterone levels on admission among patients referred for primary percutaneous coronary intervention for STEMI are associated with early and late adverse clinical outcomes, including mortality. The association between high aldosterone levels and late mortality is independent of age, heart failure, and reperfusion status. Such results underline the pivotal role of aldosterone and justify a randomized trial to assess the early administration of aldosterone antagonists in the setting of STEMI.
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Aldosterona/sangue , Eletrocardiografia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Análise Multivariada , Infarto do Miocárdio/tratamento farmacológicoRESUMO
Keeping in mind the increased pain complaints reported in anxious or depressive patients, our goal was to investigate in rats the consequences of an experimentally provoked state of anxiety/depression on pain behavior and on its underlying mechanisms. We therefore used a model of social defeat consisting of a 30 min protected confrontation followed by a 15 min physical confrontation, repeated during 4 d, that elicited symptoms close to those observed in humans with anxiety or depression. Indeed, 5 d later, animals subjected to social-defeat confrontation were characterized by a decrease of sweet-water consumption and of body weight, and a hyperactivity of the hypothalamic-pituitary-adrenal axis, suggesting that the social-defeat procedure induced a prolonged state of anxiety. Rats subjected to the social-defeat procedure showed an enhanced nociceptive behavior to the subcutaneous administration of formalin, 5 d after the last confrontation session. Because chronic treatment with the established anxiolytic chlordiazepoxide (10 mg.kg(-1).d(-1)) prevented hyperalgesia, this strongly suggested that this experimental procedure might be a suitable animal model of "anxiety-induced hyperalgesia." Hyperalgesia associated with anxiety not only was related to a significant increase of CCKLM [cholecystokinin (CCK)-like material] in frontal cortex microdialysates but also was prevented by a CCK-B receptor antagonist [4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[(tricyclo[3.3[12,17]dec-2-yloxy)-carbonyl]amino]-propyl]amino]-1-phenyethyl]amino]-4-oxo-[R-(R*, R*)]-butanoate N-methyl-D-glucamine (CI-988)] (2 mg/kg), strongly supporting the involvement of central CCKergic systems in these phenomena. Finally, combined treatments with CI-988 and morphine completely suppressed pain-related behavior, supporting the idea that the association of both compounds might represent a new therapeutic approach to reduce the increase of pain complaints highly prevalent among anxious or depressive patients.
Assuntos
Ansiedade/metabolismo , Ansiedade/psicologia , Córtex Cerebral/metabolismo , Colecistocinina/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/psicologia , Receptores da Colecistocinina/fisiologia , Animais , Peso Corporal/fisiologia , Masculino , Medição da Dor/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Objective: After an intense and repeated stress some rats become vulnerable to depression. This state is characterized by persistent low serum BDNF concentration. Our objective was to determine whether electrophysiological markers can sign vulnerability to depression. Methods: Forty-three Sprague Dawley rats were recorded with supradural electrodes above hippocampus and connected to wireless EEG transmitters. Twenty-nine animals experienced four daily social defeats (SD) followed by 1 month recovery. After SD, 14 rats had persistent low serum BDNF level and were considered as vulnerable (V) while the 15 others were considered as non-vulnerable (NV). EEG signals were analyzed during active waking before SD (Baseline), just after SD (Post-Stress) and 1 month after SD (Recovery). Results: We found that V animals are characterized by higher high θ and α spectral relative powers and lower ß2 main peak frequency before SD. These differences are maintained at Post-Stress and Recovery for α spectral relative powers and ß2 main peak frequency. Using ROC analysis, we show that low ß2 main peak frequency assessed during Baseline is a good predictor of the future state of vulnerability to depression. Conclusion: Given the straightforwardness of EEG recordings, these results open the way to prospective studies in humans aiming to identify population at-risk for depression.