Animal models in psychiatric research: The RDoC system as a new framework for endophenotype-oriented translational neuroscience.

The recently proposed Research Domain Criteria (RDoC) system defines psychopathologies as phenomena of multilevel neurobiological existence and assigns them to 5 behavioural domains characterizing a brain in action. We performed an analysis on this contemporary concept of psychopathologies in respect to a brain phylogeny and biological substrates of psychiatric diseases. We found that the RDoC system uses biological determinism to explain the pathogenesis of distinct psychiatric symptoms and emphasises exploration of endophenotypes but not of complex diseases. Therefore, as a possible framework for experimental studies it allows one to evade a major challenge of translational studies of strict disease-to-model correspondence. The system conforms with the concept of a normality and pathology continuum, therefore, supports basic studies. The units of analysis of the RDoC system appear as a novel matrix for model validation. The general regulation and arousal, positive valence, negative valence, and social interactions behavioural domains of the RDoC system show basic construct, network, and phenomenological homologies between human and experimental animals. The nature and complexity of the cognitive behavioural domain of the RDoC system deserve further clarification. These homologies in the 4 domains justifies the validity, reliably and translatability of animal models appearing as endophenotypes of the negative and positive affect, social interaction and general regulation and arousal systems' dysfunction

Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD

Adaptive neuroplasticity is a pivotal mechanism for healthy brain development and maintenance, as well as its restoration in disease- and age-associated decline. Management of mental disorders such as attention deficit hyperactivity disorder (ADHD) needs interventions stimulating adaptive neuroplasticity, beyond conventional psychopharmacological treatments. Physical exercises are proposed for the management of ADHD, and also depression and aging because of evoked brain neuroplasticity. Recent progress in understanding the mechanisms of muscle-brain cross-talk pinpoints the role of the myokine irisin in the mediation of pro-cognitive and antidepressant activity of physical exercises. In this review, we discuss how irisin, which is released in the periphery as well as derived from brain cells, may interact with the mechanisms of cellular autophagy to provide protein recycling and regulation of brain-derived neurotrophic factor (BDNF) signaling via glia-mediated control of BDNF maturation, and, therefore, support neuroplasticity. We propose that the neuroplasticity associated with physical exercises is mediated in part by irisin-triggered autophagy. Since the recent findings give objectives to consider autophagy-stimulating intervention as a prerequisite for successful therapy of psychiatric disorders, irisin appears as a prototypic molecule that can activate autophagy with therapeutic goals

Hippo Signaling: Emerging Pathway in Stress-Related Psychiatric Disorders?

Discovery of the Hippo pathway and its core components has made a significant impact on our progress in the understanding of organ development, tissue homeostasis, and regeneration. Upon diverse extracellular and intracellular stimuli, Hippo signaling regulates stemness, cell proliferation and apoptosis by a well-conserved signaling cascade, and disruption of these systems has been implicated in cancer as well as metabolic and neurodegenerative diseases. The central role of Hippo signaling in cell biology also results in prominent links to stress-regulated pathways. Genetic variations, epigenetically provoked upregulation of Hippo pathway members and dysregulation of cellular processes implicated in learning and memory, are linked to an increased risk of stress-related psychiatric disorders (SRPDs). In this review, we summarize recent findings, supporting the role of Hippo signaling in SRPDs by canonical and non-canonical Hippo pathway interactions

COMPARISON BETAXOLOL AND METOPROLOL TARTRATE THERAPIES IN PATIENTS WITH ARTERIAL HYPERTENSION ASSOCIATED WITH STABLE ANGINA

Aim. To compare antihypertensive, antianginal and antiischemic efficacy of β1-selective adrenoblockers (betaxolol and metoprolol tartrate) in patients with arterial hypertension (HT) of 1-2 degree associated with stable angina class II.Material and methods. 100 patients (aged 23-66 y.o.) with HT associated with stable angina or without angina were involved in the study. Patients were randomized into 2 groups (G1 and G2). G1 patients were treated with betaxolol, and G2 patients – with metoprolol tartrate. Ambulatory BP and electrocardiogram monitoring, exercise stress-test, echocardiography, evaluating of respiratory function, blood analysis was performed initially and in 30 and 90 days of treatment.Results. Target BP level was reached in 44 (88%) patients treated with betaxolol (average daily dose 10±4 mg). 34 patients of G1 took 10 mg daily. Target BP level was reached in 41 (82%) patients treated with metoprolol tartrate (average daily dose 150±27 mg). 30 patients of G2 took 150 mg daily. Exercise tolerance increased and a number of ischemic ST segment depressions reduced significantly in both groups. There were no significant differences in antihypertensive, antianginal, and antiischemic efficacy between groups.Conclusion. Betaxolol advantage is an ability to maintain target BP level more than 24 hours. A possibility to take betaxolol once a day raises patient’s compliance with therapy

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.Fil: Dedic, Nina. Max Planck Institute Of Psychiatry; AlemaniaFil: Kühne, Claudia. Max Planck Institute Of Psychiatry; AlemaniaFil: Jakovcevski, Mira. Max Planck Institute Of Psychiatry; AlemaniaFil: Hartmann, Jakob. Max Planck Institute Of Psychiatry; AlemaniaFil: Genewsky, Andreas J.. Max Planck Institut Of Psychiatry; AlemaniaFil: Gomes, Karina S.. Max Planck Institute Of Psychiatry; AlemaniaFil: Anderzhanova, Elmira. Max Planck Institute Of Psychiatry; AlemaniaFil: Pöhlmann, Max L.. Max Planck Institute Of Psychiatry; AlemaniaFil: Chang, Simon. Max Planck Institute Of Psychiatry; AlemaniaFil: Kolarz, Adam. Max Planck Institute Of Psychiatry; AlemaniaFil: Vogl, Annette M.. Max Planck Institute Of Psychiatry; AlemaniaFil: Dine, Julien. Max Planck Institute Of Psychiatry; AlemaniaFil: Metzger, Michael W.. Max Planck Institute of Psychiatry; ArmeniaFil: Schmid, Bianca. Max Planck Institute Of Psychiatry; AlemaniaFil: Almada, Rafael C.. Max Planck Institute Of Psychiatry; AlemaniaFil: Ressler, Kerry J.. Harvard Medical School; Estados UnidosFil: Wotjak, Carsten T.. Max Planck Institute Of Psychiatry; AlemaniaFil: Grinevich, Valery. University of Heidelberg; AlemaniaFil: Chen, Alon. Max Planck Institute Of Psychiatry; AlemaniaFil: Schmidt, Mathias V.. Institute Of Developmental Genetics, Helmholtz Zentrum; AlemaniaFil: Wurst, Wolfgang. German Center for Neurodegenerative Diseases; AlemaniaFil: Refojo, Damian. Max Planck Institute Of Psychiatry; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Deussing, Jan M.. Max Planck Institute Of Psychiatry; Alemani

Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia

Background Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus.Methods In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed.Results Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole.Conclusions Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation

Role of Dopaminergic and Glutamatergic Systems of the Striatum in the Mechanisms of d-Amphetamine and Ammonia Neurotoxicity

Väitöstyössä tutkittiin amfetamiinin ja sydnokarbin aiheuttamia kemiallisia muutoksia rotan aivojuoviossa. Sydnokarb on Venäjällä kehitetty psykostimulatti. Se ei aiheuta riippuvuutta niin kuin amfetamiini, eikä sitä siksi käytetä huumausaineena. Molemmat lääkkeet lisäsivät hermovälittäjäaineiden dopamiinin ja glutamiinin solunulkoista pitoisuutta ja kiihdyttivät dopamiinin aineenvaihtoa. Ne lisäsivät myös hydroksyyliradikaalien muodostumista ja aiheuttivat stereotyyppistä käyttäytymistä. Dopamiinin antagonisti sulpiridi esti dopamiinin aiheuttamia neurotoksisia muutoksia, mutta lisäsi stereotyyppistä käytöstä. Sydnokarb osoittautui vähemmän neurotoksiseksi kuin amfetamiini, koska sen aiheuttamat muutokset olivat vähäisempiä ja tulivat hitaammin. Aivojen ammoniakkipitoisuuden liiallinen lisääntyminen johtaa koomaan ja lopulta kuolemaan, kun dopamiini- ja glutamiinivälittäjäaineiden toiminta häiriytyy. Ammoniumioneja sisältävän liuoksen infuusio lisäsi nopeasti dopamiinin ja sen aineenvaihduntatuotteiden vapautumista aivojuoviosta. Sen esti inhiboiva neuromodulaattori tauriini. Ammoniakki aktivoi myös liiallisesti glutamaatin N-metyl-D-aspartaattireseptoreita, mikä edelleen lisää hydroksyyyliradikaalien ja syklisen guanosiinitrifostaatin muodostumista. Tauriini esti nämäkin muutokset. Tutkimus on ensimmäinen suora osoitus elävällä eläimellä siitä, että tauriini on tehokas hermostoa suojaava aine.The study focused on the chemical changes in the rat striatum induced by d-amphetamine and sydnocarb. Sydnocarb is a Russian-invented psychostimulant that is not addictive and thus less susceptible for abuse. Both drugs increased the extracellular concentrations of dopamine and glutamate neurotransmitters and fomented dopamine metabolism. They also enhanced hydroxyl radical formation and induced stereotypic behavior. The dopamine antagonist sulpiride attenuated the neurotoxic effects of amphetamine but enhanced stereotypy. Sydnocard proved to be less neurotoxic than amptehamine, since its neurotoxic effects were less pronounced with slower onset. The excessive increase in brain ammonia leads to coma and eventual death when the functions of dopamine and glutamate transmitters are seriously perturbed. Infusion of ammonium ions greatly enhanced liberation of dopamine and its metabolites from the striatum. These effects were blocked by taurine, an inhibitory neuromodulator. Ammonia also overactivates the N-methyl-D-aspartate class of glutamate receptors, which further enhances the formation of hydroxyl radicals and cyclic guanosine triphosphate. Taurine also prevented these changes. The present study is the first to show in a living animal that taurine is an effective neuroprotectant

Role of Dopaminergic and Glutamatergic Systems of the Striatum in the Mechanisms of d-Amphetamine and Ammonia Neurotoxicity

Väitöstyössä tutkittiin amfetamiinin ja sydnokarbin aiheuttamia kemiallisia muutoksia rotan aivojuoviossa. Sydnokarb on Venäjällä kehitetty psykostimulatti. Se ei aiheuta riippuvuutta niin kuin amfetamiini, eikä sitä siksi käytetä huumausaineena. Molemmat lääkkeet lisäsivät hermovälittäjäaineiden dopamiinin ja glutamiinin solunulkoista pitoisuutta ja kiihdyttivät dopamiinin aineenvaihtoa. Ne lisäsivät myös hydroksyyliradikaalien muodostumista ja aiheuttivat stereotyyppistä käyttäytymistä. Dopamiinin antagonisti sulpiridi esti dopamiinin aiheuttamia neurotoksisia muutoksia, mutta lisäsi stereotyyppistä käytöstä. Sydnokarb osoittautui vähemmän neurotoksiseksi kuin amfetamiini, koska sen aiheuttamat muutokset olivat vähäisempiä ja tulivat hitaammin. Aivojen ammoniakkipitoisuuden liiallinen lisääntyminen johtaa koomaan ja lopulta kuolemaan, kun dopamiini- ja glutamiinivälittäjäaineiden toiminta häiriytyy. Ammoniumioneja sisältävän liuoksen infuusio lisäsi nopeasti dopamiinin ja sen aineenvaihduntatuotteiden vapautumista aivojuoviosta. Sen esti inhiboiva neuromodulaattori tauriini. Ammoniakki aktivoi myös liiallisesti glutamaatin N-metyl-D-aspartaattireseptoreita, mikä edelleen lisää hydroksyyyliradikaalien ja syklisen guanosiinitrifostaatin muodostumista. Tauriini esti nämäkin muutokset. Tutkimus on ensimmäinen suora osoitus elävällä eläimellä siitä, että tauriini on tehokas hermostoa suojaava aine.The study focused on the chemical changes in the rat striatum induced by d-amphetamine and sydnocarb. Sydnocarb is a Russian-invented psychostimulant that is not addictive and thus less susceptible for abuse. Both drugs increased the extracellular concentrations of dopamine and glutamate neurotransmitters and fomented dopamine metabolism. They also enhanced hydroxyl radical formation and induced stereotypic behavior. The dopamine antagonist sulpiride attenuated the neurotoxic effects of amphetamine but enhanced stereotypy. Sydnocard proved to be less neurotoxic than amptehamine, since its neurotoxic effects were less pronounced with slower onset. The excessive increase in brain ammonia leads to coma and eventual death when the functions of dopamine and glutamate transmitters are seriously perturbed. Infusion of ammonium ions greatly enhanced liberation of dopamine and its metabolites from the striatum. These effects were blocked by taurine, an inhibitory neuromodulator. Ammonia also overactivates the N-methyl-D-aspartate class of glutamate receptors, which further enhances the formation of hydroxyl radicals and cyclic guanosine triphosphate. Taurine also prevented these changes. The present study is the first to show in a living animal that taurine is an effective neuroprotectant