Antidepressant effects of 3-(3,4-methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide involve TSPO-mediated mitophagy signalling pathway.

Piper laetispicum C. DC is one of the Chinese herbal medicines used for alleviating depressive disorders. G11-5 [3-(3, 4-methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide] is synthesized based on the chemical structure of an active integrant of Piper laetispicum C. DC. The present study assessed the antidepressant effect of G11-5 and investigated the underlying mechanism with learned helplessness (LH) and social defeat stress (SDS) mice model of depression. In the LH model, mice were exposed to 60 inescapable electric shocks once a day for three consecutive days followed by 2-week drug administration and helpless behaviour assessment. In the SDS model, mice were subjected to repeated social defeat by an aggressive CD-1 mouse once a day for consecutive 10 days. Following oral administration for 2 weeks, the mice were subjected to a series of behavioural tests including social interaction test. G11-5 significantly decreased the number of escape failures induced by LH paradigm, meanwhile increased the social interaction ratio and shortened the immobility time in forced swimming test for the SDS-exposed mice, suggesting remarkable antidepressant effect. Moreover, G11-5 ameliorated the changes in mitophagy-related proteins induced by two stress exposures and restored retrograde axonal transport and neurotransmitter release. Our findings suggested that G11-5 exhibited an obvious antidepressant through TSPO-mediated mitophagy pathway.

Abandonado: estudo comparativo dos medicamentos da materia medica homeopatica / Abandoned: comparative study of homeopathic medicines

O tema abandonado despertou o interesse pela necessidade de conhecer sua relação com rubricas constantes em compêndios homeopáticos (Matérias Médicas, Repertórios). Após a seleção dos medicamentos, realizou-se estudo das respectivas patogenesias, acompanhado de comparações entre a manifestação de sintomas semelhantes em medicamentos diversos. O presente trabalho ressalta a Homeopatia como proposta terapêutica, tornando-se importante ferramenta no tratamento de pacientes com a queixa de abandono em situações emergenciais, o que permite a retirada mais precoce de medicação psicotrópica, com consequente melhora da qualidade de suas vidas.(AU)

The abandoned theme aroused interest in the need to know its relationship with constant rubrics in homeopathic textbooks (Medical articles, Repertoires). After the selection of medicinal products, a study of the respective pathogeneses was carried out, accompanied by comparisons between the manifestation of similar symptoms in different medications. The present work emphasizes Homeopathy as a therapeutic proposal, becoming an important tool in the treatment of patients with complaints of ABANDONMENT, in emergency situations, thus allowing the earlier withdrawal of psychotropic medication, improving the quality if their lives.(AU)

Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF.

Curculigoside (CUR) is the main active component of traditional Chinese medicine Curculigoorchioides Gaertn (Xianmao in Chinese), which exhibits a variety of pharmacological activities. In this study we investigated the effects of CUR on fear extinction and related depression-like behaviors in mice. In fear conditioning task, we found that administration of CUR (1.6, 8, 40 mg·kg-1·d-1, ip, for 7 days) did not affect memory consolidation, but CUR at higher doses (8, 40 mg·kg-1·d-1) significantly facilitated fear extinction, especially on D3 and D4. Moreover, CUR administration significantly ameliorated the fear conditioning-induced depression-like behaviors, likely through promoting fear extinction. We showed that CUR increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) in the hippocampus, and activated protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) signaling pathway. Administration of the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF, 5 mg·kg-1·d-1, ip) also facilitated fear extinction, ameliorated depression-like behaviors. We established a mouse learned helplessness (LH) model to evaluate the antidepressant activity of CUR. The spatial memory was assessed in Morris water maze. We showed that LH-induced depression-like behaviors, including prolonged immobility times in forced swim and tail suspension tests as well as spatial memory impairments; LH also downregulated BDNF expression and the Akt-mTOR signaling pathway in the hippocampus. Administration of CUR (1.6, 8, 40 mg·kg-1·d-1, ip, for 14 days) or 7,8-DHF (5 mg·kg-1·d-1, ip, for 3 days) prevented LH-induced depression-like behaviors and promoted BDNF expression and the Akt-mTOR signaling pathway. In conclusion, CUR can accelerate the fear memory extinction and ameliorate depression-like behaviors in mice via promoting BDNF expression and activating the Akt-mTOR signaling pathway in the hippocampus.

The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.

Neural Plasticity Associated with Hippocampal PKA-CREB and NMDA Signaling Is Involved in the Antidepressant Effect of Repeated Low Dose of Yueju Pill on Chronic Mouse Model of Learned Helplessness.

Yueju pill is a traditional Chinese medicine formulated to treat syndromes of mood disorders. Here, we investigated the therapeutic effect of repeated low dose of Yueju in the animal model mimicking clinical long-term depression condition and the role of neural plasticity associated with PKA- (protein kinase A-) CREB (cAMP response element binding protein) and NMDA (N-methyl-D-aspartate) signaling. We showed that a single low dose of Yueju demonstrated antidepressant effects in tests of tail suspension, forced swim, and novelty-suppressed feeding. A chronic learned helplessness (LH) protocol resulted in a long-term depressive-like condition. Repeated administration of Yueju following chronic LH remarkably alleviated all of depressive-like symptoms measured, whereas conventional antidepressant fluoxetine only showed a minor improvement. In the hippocampus, Yueju and fluoxetine both normalized brain-derived neurotrophic factor (BDNF) and PKA level. Only Yueju, not fluoxetine, rescued the deficits in CREB signaling. The chronic LH upregulated the expression of NMDA receptor subunits NR1, NR2A, and NR2B, which were all attenuated by Yueju. Furthermore, intracerebraventricular administration of NMDA blunted the antidepressant effect of Yueju. These findings supported the antidepressant efficacy of repeated routine low dose of Yueju in a long-term depression model and the critical role of CREB and NMDA signaling.

Instant and Persistent Antidepressant Response of Gardenia Yellow Pigment Is Associated with Acute Protein Synthesis and Delayed Upregulation of BDNF Expression in the Hippocampus.

Gardenia yellow pigment (GYP) is a collection of compounds with shared structure of crocin, which confers antidepressant activity. GYP is remarkably enriched in Gardenia jasminoides Ellis, implicated in rapid antidepressant effects that are exerted through enhanced neuroplasticity. This study aims to investigate the rapid antidepressant-like activity of GYP and its underlying mechanism. After the optimal dose was determined, antidepressant responses in tail suspension test or forced swim test were monitored at 30 min, 1 day, 3 days, and 7 days post a single GYP administration. Rapid antidepressant potential was tested using learned helplessness paradigm. The expression of proteins involved in hippocampal neuroplasticity was determined. The effect of blockade of protein synthesis on GYP's antidepressant response was examined. Antidepressant response was detected at 30 min, and lasted for at least 3 days post a single administration of GYP. A single administration of GYP also reversed the deficits in learned helplessness test. Thirty minutes post GYP administration, ERK signaling was activated, and its downstream effector phosphorylated eukaryotic elongation factor 2 was inhibited, contributing to increased protein translation. Expression of synaptic proteins GluR1 and synapsin 1 was upregulated. Blockade of protein synthesis with anisomycin blunted the immediate antidepressant response of GYP. CREB signaling and BDNF expression were upregulated at 24 h, but not at 30 min. In conclusion, GYP-induced immediate antidepressant response was dependent on synthesis of proteins, including synaptic proteins. This was followed by enhanced expression of CREB and BDNF, which likely mediated the persistent antidepressant responses.

Wuling powder prevents the depression-like behavior in learned helplessness mice model through improving the TSPO mediated-mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuling powder (trade name: Wuling capsule), a traditional Chinese medicine (TCM), was extracted from mycelia of precious Xylaria Nigripes (Kl.) Sacc by modern fermentation technology, and has been claimed to be fully potent in improving the signs of insomnia and cognitive deficits. Moreover, Wuling capsule was effective in treating post-stroke and orther co-cormbid depression both in clinical and in basic research. In order to clarify the molecular mechanisms of the antidepressant effect of Wuling powder, we established learned helplessness (LH) depression animal model and focused on 18kDa translocator protein (TSPO) mediated-mitophagy pathway. MATERIALS AND METHODS: Mice were exposed to the inescapable e-shock (IS) once a day for three consecutive days to establish the LH model. Then mice were orally administered Wuling powder for 2 weeks. For the behavioral assessment, Shuttle box test, novelty suppressed feeding test (NSF) and forced swimming test (FST) were performed. Following the behavioral assessment, we assessed the protein expression level that were related to TSPO-mediated mitophagy signaling pathway by Western blotting analysis. Finally, immunohistochemistry method was used to assess the neuroprotective effects of Wuling powder. RESULTS: Compared with mice that were subjected to inescapable e-shock, Wuling powder exhibited antidepressant effect in the multiple behavioral tests. In addition, Wuling powder altered the expression level of multiple proteins related to TSPO-mediated mitophagy signaling pathway. CONCLUSIONS: Our results suggested that Wuling powder exhibited an obvious antidepressant effect, which could be due to the improvement of TSPO-mediated mitophagy signaling pathway.

Sensitivity during the forced swim test is a key factor in evaluating the antidepressant effects of abscisic acid in mice.

Abscisic acid (ABA), a crucial phytohormone, is distributed in the brains of mammals and has been shown to have antidepressant effects in the chronic unpredictable mild stress test. The forced swim test (FST) is another animal model that can be used to assess antidepressant-like behavior in rodents. Here, we report that the antidepressant effects of ABA are associated with sensitivities to the FST in mice. Based on mean immobility in the 5-min forced swim pre-test, ICR mice were divided into short immobility mice (SIM) and long immobility mice (LIM) substrains. FST was carried out 8 days after drug administration. Learned helplessness, as shown by increased immobility, was only observed in SIM substrain and could be prevented by an 8-day ABA treatment. Our results show that ABA has antidepressant effects in SIM substrain and suggest that mice with learned helplessness might be more suitable for screening potential antidepressant drugs.

Antidepressant-like effects and mechanism of action of SYG in depression model in rats.

OBJECTIVES: The present study aimed to evaluate whether SYG, a Chinese herbal formula, could produce antidepressant-like effects in learned helplessness (LH) model and chronic mild stress (CMS) model in rats. The mechanism underlying the antidepressant-like action was investigated by exploring BDNF signaling way in the hippocampus. MATERIAL AND METHODS: SYG was administrated for 5 consecutive days (100 and 200 mg/kg/day, intragastrically) in the learned helplessness model; SYG was administered daily by gastric gavages during both the 5-week stress session and behavior tests periods in the chronic mild stress model (100 and 200 mg/kg). The serum corticosterone level was measured in the learned helplessness model. Levels of BDNF and Tyrosine-related kinase B (TrkB), were evaluated in the hippocampus of chronic mild stress model. RESULTS: A deficit in avoidance learning and higher corticosterone level were observed in learned helplessness rats. SYG significantly reduced this deficit and reversed the corticosterone alteration. CMS induced significant reduction of sucrose intake in the sucrose preference test, an increased latency to feed in the novelty-suppressed feeding test and an increased immobility time in the forced swim test as compared to the control. It was also found that BDNF and TrkB levels were decreased in CMS model. Chronic treatment of SYG significantly suppressed the behavioral changes and up-regulated the BDNF signal pathway in the hippocampus. CONCLUSION: Our results suggest that SYG alleviates depression induced by LH and CMS model. The antidepressant-like activity of SYG is likely mediated by activation the BDNF signal pathway in the hippocampus.

Gastrodin ameliorates depressive-like behaviors and up-regulates the expression of BDNF in the hippocampus and hippocampal-derived astrocyte of rats.

Gastrodin (GAS), a main constituent of a Chinese herbal medicine Tian ma, has been shown to be effective in treating various mood disorders. The purpose of the present study was to assess the effects of GAS on alleviating depressive-like behaviors in a rat model of chronic unpredictable stress (CUS) and regulating the expression of BDNF in the hippocampus and hippocampal-derived astrocyte from Sprague-Dawley (SD) rats. Following CUS, rats were intraperitoneally administered gastrodin (50, 100, or 200 mg/kg daily) or vehicle for 2 weeks. Rats were then experienced sucrose preference test and forced swim test. The expressions of GFAP and BDNF in the hippocampus were evaluated. In addition, hippocampal astrocytes were isolated from neonatal SD rats and exposed to different concentrations of GAS (sham, 5, 10, 20, 50 and 100 µg/mL) for 48 and 72 h before the cell viability and the levels of pERK1/2 and BDNF were analyzed. Furthermore, the cell viability was also tested after exposure to serum-free condition that contain different concentrations of GAS for 48 and 72 h. GAS administration (100 and 200 mg/kg daily) reversed depressive-like behaviors in rats exposed to CUS paradigm and restored the expression of GFAP and BDNF in the hippocampus. Moreover, in vitro experiments revealed that GAS did not increase the cell viability of astrocytes but protected it from 72 h's serum-free damage at the dosage 20 µg/mL. Increased levels of ERK1/2 phosphorylation and BDNF protein were also observed after GAS (20 µg/mL) treatment for 72 h. These results indicate that gastrodin possesses antidepressant effect. The changes of the astrocyte activation and the level of BDNF may play a critical role in the pharmacological action of GAS.

Treating the psychological sequelae of proactive drug-facilitated sexual assault: knowledge building through systematic case based research.

BACKGROUND: Drug-facilitated sexual assault (DFSA) has emerged as a distinct category of sexual victimization and precipitates posttraumatic stress disorder (PTSD). Few studies have examined the distinct psychological aspects of PTSD caused by DFSA. Gauntlett-Gilbert, Keegan and Petrak (2004) represent a notable exception and draw on cases, from their clinical experience, treated using Ehlers and Clarks' (2000) cognitive therapy (CT). AIMS: This paper aims to further develop and refine clinical knowledge on CT for PTSD arising from DFSA and advance the findings of Gauntlett-Gilbert et al. (2004). METHOD: Systematic case based research was used to investigate the applicability of CT for PTSD related to DFSA. Three survivors were treated with CT within the South African context. RESULTS: The case series corroborated existing findings but also documented the presence of somatic and visual intrusions among survivors with partial or complete amnesia for rape and illustrated the utility of imagery interventions in targeting intrusions. The study highlighted the role of physical paralysis in DFSA in compounding helplessness/powerlessness and the necessity of enhancing physical agency and building social support. CONCLUSION: Distinctive aspects of PTSD related to DFSA can be effectively treated by adapting CT to suit this population group.

Selective breeding for helplessness in rats alters the metabolic profile of the hippocampus and frontal cortex: a 1H-MRS study at 9.4 T.

In humans metabolic changes, particularly in frontal areas of the brain, accompany depressive disorders, but few studies were conducted in animal models of depression. We used hydrogen-1 magnetic resonance spectroscopy at 9.4 T to measure the metabolic profiles of the hippocampus and frontal cortex in congenital learned helpless (cLH) and wild-type (WT) rats. The learned helplessness model of depression exposes animals to uncontrollable stress to induce changes in emotion, cognition and behaviour, but cLH rats were selectively bred to show changes in behaviour even without exposure to uncontrollable stress. Experimentally naive male 8- to 10-wk-old cLH (n = 10) and WT rats (n = 22) underwent spectroscopy and were exposed to uncontrollable stress 1 wk after the scan. We found that cLH compared to WT rats had lower levels of glutamate in the hippocampus and lower levels of choline-containing compounds in the hippocampus and frontal cortex, but higher levels of taurine and phosphocreatine in these regions, pointing to compensatory efforts of the brain to reduce excitotoxic potential and to increase neuroprotection and energy, possibly as a result of cellular stress and damage. The reduction in choline-containing phospholipids might represent a source or correlate of such stress. Overall, the results indicate that metabolic abnormalities are present in animals with a predisposition to helplessness even without exposure to explicit stress and may help identify non-invasive biomarkers in individuals who are prone to depression.

Integrating palliative care into comprehensive cancer care.

While there are operational, financial, and workforce barriers to integrating oncology with palliative care, part of the problem lies in ourselves, not in our systems. First, there is oncologists' "learned helplessness" from years of practice without effective medications to manage symptoms or training in how to handle the tough communication challenges every oncologist faces. Unless they and the fellows they train have had the opportunity to work with a palliative care team, they are unlikely to be fully aware of what palliative care has to offer to their patients at the time of diagnosis, during active therapy, or after developing advanced disease, or may believe that, "I already do that." The second barrier to better integration is the compassion fatigue many oncologists develop from caring for so many years for patients who, despite the oncologists' best efforts, suffer and die. The cumulative grief oncologists experience may go unnamed and unacknowledged, contributing to this compassion fatigue and burnout, both of which inhibit the integration of oncology and palliative care. Solutions include training fellows and practicing oncologists in palliative care skills (eg, in symptom management, psychological disorders, communication), preventing and treating compassion fatigue, and enhancing collaboration with palliative care specialists in caring for patients with refractory distress at any stage of disease. As more oncologists develop these skills, process their grief, and recognize the breadth of additional expertise offered by their palliative care colleagues, palliative care will become integrated into comprehensive cancer care.

Depressive-like behavior in adolescents after maternal separation: sex differences, controllability, and GABA.

Exposure to adversity during development is an identified risk factor for depression later in life. In humans, early adversity accelerates the onset of depressive symptoms, which manifest during adolescence. Animal studies have used maternal separation as a model of early adversity to produce adult depressive-like behaviors, but have yet to examine these behaviors during adolescence. Moreover, the nature of depressive-like behaviors has not been well characterized in this model. Here, we used the triadic model of learned helplessness to understand controllability, helplessness, and motivational factors following maternal separation in male and female adolescent rats. We found sex-dependent changes in the effects of separation, with males demonstrating loss of controllability in an escapable shock condition, whereas females demonstrated motivational impairment in a no-shock condition. The effect, however, did not endure as adult females were no longer helpless. Reductions in parvalbumin, a GABAergic marker, in the prefrontal cortex of separated subjects relative to age-matched controls were evident and paralleled depressive-like behavior. Understanding the risk factors for depression, the nature of depressive-like behaviors, and their unique sex dependency may ultimately provide insight into improved treatments.

Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression.

The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates NMDA-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the GluN2B subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestations of depression.

Chronic daily headache: helping adolescents help themselves with self-hypnosis.

Although the evidence is clear that hypnosis has been an effective treatment for recurrent headaches in children, review of the literature revealed no previous reports of hypnosis for youth with the condition of chronic daily headache. Two adolescents with continuing chronic daily headaches were taught self-hypnosis through careful attention to individual strengths and finding the hypnotic elements within the clinical encounters. Self-reports of intensity, frequency, and duration of headaches described substantial benefit from learning and practicing self-hypnosis after little to no benefit from pharmacologic and other nonpharmacologic therapies. These results and analogous success with several other adolescents with chronic daily headache support the further use of self-hypnosis training for this condition. As a self-regulation technique that is quickly and easily learned by most young people, self-hypnosis training holds considerable promise for effectively treating and perhaps preventing chronic daily headaches in children and adolescents.

[A different person in 2 minutes]. / Ein anderer Mensch in 2 Minuten.

I would like to describe the initial extreme physical and psychological effects of my posttraumatic stress disorder that appeared after multiple shocks from an implantable cardioverter-defibrillator, my surprise about my physical awareness, which I and apparently also the physicians could not understand, the feeling of helplessness, the lack of knowledge, the ignorance, and the unfairness of some of the physicians concerning my psychological illness, feelings of being stamped as a psychopath, not being believed, and being let down, my improvements during the course of the last 6 years, my current condition, and my appeal to physicians that better care be offered to patients with a similar illness.

Green odor and depressive-like state in rats: toward an evidence-based alternative medicine?

It is widely accepted that mental stress is an important factor in the development of psychological disorders such as depression. On pre-existing evidence, the so-called green odor may have a relieving and sedative effect on animals exposed to stressful situations. Using two behavioral models of depression, the forced-swim test and learned helplessness paradigm, we investigated whether inhalation of green odor (a 50:50 mixture of trans-2-hexenal and cis-3-hexenol) might alleviate and/or prevent experimentally induced depressive-like states in rats. A 3-min swim every day for 7 days resulted in significant prolongation of immobility time (vs. day 1). Inhaling green odor, but not vehicle, thereafter for 10 days (without swimming) led to the prolonged immobility time being significantly reduced and the hippocampal level of brain-derived neurotrophic factor (BDNF) being significantly increased. In the learned helplessness paradigm, the failure number and time spent in the shock compartment seen in the active avoidance test were both significantly attenuated in those rats that inhaled green odor for 11 days after the postshock screening test (vs. vehicle-exposed rats). Finally, for 10 consecutive days rats continuously exposed to green odor or vehicle swam for 3 min/day. Immobility time was significantly shorter in the green-odor group than in the vehicle-exposed group on days 6-10. These results suggest that green odor has not only a therapeutic, but also a preventive effect on depressive-like states in rats. These effects may be at least in part due to a green odor-induced upregulation of BDNF in the hippocampus.