Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress.

BACKGROUND: Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABAA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown. METHODS: We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. RESULTS: The expression of δ subunit-containing GABAA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS. CONCLUSIONS: Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala.

BACKGROUND: Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABAA (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects. METHODS: We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states. RESULTS: We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABAA receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6-12 Hz) through δ-containing GABAA receptors, a mechanism distinct from other GABAA positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress. CONCLUSIONS: Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

Fatores de risco associados ao agravamento de sepse em pacientes em Unidade de Terapia Intensiva / Risk factors associated to sepsis severity in patients in the Intensive Care Unit

Resumo Introdução a sepse é um grave problema de saúde pública e uma das principais causas de morte em Unidade de Terapia Intensiva (UTI). Objetivo este trabalho avaliou o agravamento e a mortalidade de pacientes sepse em UTI, relacionando aos fatores de risco, diferentes etiologias e terapêuticas. Metodologia O estudo foi observacional descritivo, e avaliou os casos de sepse (sepse, sepse severa e choque séptico) no período de janeiro de 2009 a dezembro de 2010. Resultados dos 212 pacientes internados em UTI, 181 apresentaram sepse nas diferentes gravidades, cuja mortalidade por sepse na UTI foi de 63%, principalmente nos pacientes com choque séptico (53%), seguida da sepse grave (8,3%). Além disso, os fatores de risco associados ao agravamento da sepse foram: idade superior que 65 anos, maior tempo médio de internação na UTI, elevada frequência de comorbidades e a utilização de procedimentos invasivos. O maior consumo de antibióticos foi de carbapenêmicos, e as principais cepas multirresistentes isoladas foram MRSA, VRE, P. aeruginosa e A. baumannii resistente a carbapenêmicos. Conclusão este estudo mostrou uma elevada mortalidade por sepse na UTI, principalmente em pacientes com choque séptico com comorbidades, que foram submetidos aos procedimentos invasivos e com maior tempo de internação.

Abstract Introduction sepsis is a serious public health problem, leading cause of death in Intensive Care Unit (ICU) worldwide. Objective this study evaluated the aggravation and mortality of sepsis patients in ICU, relating to risk factors, different etiologies and therapies. Methodology the study was observational descriptive, and evaluated the cases of sepsis (sepsis, severe sepsis and septic shock) from January 2009 to December 2010. Results of the 212 patients hospitalized in ICU, 181 presented sepsis at different severities, whose sepsis mortality in the ICU was 63%, especially in patients with septic shock (53%), followed by severe sepsis (8.3%). Moreover, the risk factors associated with the aggravation of sepsis were older than 65 years, longer ICU hospitalization time, high frequency of comorbidities and the use of invasive procedures. The highest consumption of antibiotics was carbapenems, and the main isolated multiresistant strains were MRSA, VRE, P. aeruginosa and A. baumannii resistant to carbapenems. Conclusion this study showed a high mortality from sepsis patients in the ICU, especially in patients with septic shock with comorbidities, who underwent invasive procedures and longer hospitalization time.