You-Zhi Zhang

The total flavonoids extracted from Xiaobuxin-Tang up-regulate the decreased hippocampal neurogenesis and neurotrophic molecules expression in chronically stressed rats.

Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, has been used for the treatment of depressive disorders for centuries in China. Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of XBXT reversed behavioral alterations and serotonergic dysfunctions in chronically stressed rats. Recently, accumulating studies have suggested the behavioral effects of chronic antidepressants treatment might be mediated by the stimulation of hippocampal neurogenesis. In present study, we explored the effect of XBXT-2 on hippocampal neurogenesis and neurotrophic signal pathway in chronically stressed rats. Our immunohistochemistry results showed that concomitant administration of XBXT-2 (25, 50 mg/kg, p.o., 28 days, the effective doses for behavioral responses) significantly increased hippocampal neurogenesis in chronically stressed rats. Four weeks after BrdU injection, result in double immunofluorescence labeling showed that some of the newly generated cells in hippocampus co-expressed with NSE or GFAP, markers for neurons or astrocytes, respectively. Furthermore, XBXT-2 treatment reserved stress-induced decrease of hippocampal BDNF and pCREB (Ser133) expression, two important factors which were closely related to hippocampal neurogenesis. As a positive control drug, imipramine (10 mg/kg, p.o.) exerted same effects. In conclusion, the increase of neurogenesis, as well as expression of BDNF and pCREB in hippocampus may be one of the molecular and cellular mechanisms underlying the antidepressant action of XBXT-2.

Role for serotonin in the antidepressant-like effect of a flavonoid extract of Xiaobuxin-Tang.

Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, has been used for the treatment of depressive disorders for centuries in China. Herein, we explored the antidepressant-like effect and its monoaminergic mechanism of the total flavonoids (XBXT-2) isolated from the extract of XBXT. In present study, single XBXT-2 (25, 50, 100 mg/kg, p.o.) administration significantly potentiated the mouse head-twitch response induced by 5-hydroxytryptophan (5-HTP, a metabolic precursor to serotonin), and also, decreased the immobility time in mouse tail suspension test, which was completely prevented by p-chlorophenylalanine (PCPA, an inhibitor of serotonin synthesis) pretreatment. However, single treatment with XBXT-2 had no effect on yohimbine toxicity and high dose of apomorphine-induced hypothermia in mice. These results indicated that acute treatment with XBXT-2 produced serotonergic, but not noradrenergic activation. In addition, chronic XBXT-2 (25, 50 mg/kg, p.o., 28 days) treatments significantly reversed the depressive-like behaviors in chronically mildly stressed (CMS) rats, including the reduced sucrose preference, deficient locomotor activity and prolonged latency to novelty-suppressed feeding. Furthermore, XBXT-2 normalized the neurotransmitter changes, including the decreased serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in hippocampus and prefrontal cortex in CMS rats. These findings confirm the antidepressant-like effect of XBXT-2 in CMS model of rats, which may be primarily based on its serotonergic activation.

RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects.

Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant‐like and cognition‐enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform‐specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long‐form PDE4D variants mediate antidepressant‐like and cognition‐enhancing effects, but are irrespective with emesis.

Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

AbstractAim:To explore the mechanism of agmatines antidepressant action.Methods:Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period. The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically. For bromodeo-xyuridine (BrdU; thymidine analog as a marker for dividing cells) labeling, the mice were injected with BrdU (100 mg/kg, ip, twice per d for 2 d), and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry. The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay.Results:After the onset of chronic stress, the locomotor activity of the mice in the open field significantly decreased, while coadministration of agma-tine10 mg/kg (po) blocked it. Furthermore, the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons. In vitro treatment with agmatine 0.1–10 umol/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner.Conclusion:We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice. This may be one of the important mechanisms involved in agmatines antidepressant action.

Antidepressant-like effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor

SNRIs (serotonin and norepinephrine reuptake inhibitors) have been proposed to exert increased therapeutic efficacy or be faster acting compared to commonly used antidepressants. In this study, we performed in vitro binding and uptake assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of the compound 071031B; we also performed cytotoxicity tests using HepG2 cells and SH-SY5Y cells to predict the toxicity of 071031B. In vitro, 071031B had high affinity for both serotonin transporters and norepinephrine transporters prepared from rat cortex tissue (Ki=2.68 and 1.09 nM, respectively) and recombinant cells (Ki=1.57 and 0.36 nM, respectively). Moreover, 071031B also potently inhibited the uptake of serotonin (5-HT) and norepinephrine (NE) into rat cortical synaptosomes (Ki=1.99 and 1.09 nM, respectively) and recombinant cells (Ki=3.23 and 0.79 nM, respectively). In vivo, acute administration of 071031B dose-dependently reduced the immobility time in the tail suspension test in mice and the forced swimming test in mice and rats with higher efficacy than duloxetine and showed no stimulatory effect on the locomotor activity. Chronic 071031B treatment (5 or 10mg/kg) significantly reversed depressive-like behaviors in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged latency to begin eating. Furthermore, 071031B also exhibited lower cytotoxicity in HepG2 cells and SH-SY5Y cells in vitro than duloxetine. These findings suggest that 071031B is a novel, balanced serotonin and norepinephrine reuptake inhibitor, with more potent antidepressant effects and lower hepatotoxicity and neurotoxicity in vitro than duloxetine.

Inhibition of N-methyl-D-aspartate receptor function appears to be one of the common actions for antidepressants.

In order to explore the possible common action mechanisms of three kinds of classical antidepressants, inhibition of drugs on the N-methyl-D-aspartate (NMDA)–Ca2–nitric oxide synthase (NOS) signal pathway was observed. With 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, classical antidepressants, desipramine (1, 10 M), fluoxetine (0.625–10 M) or moclobemide (2.5, 10 M) antagonized NMDA 300 M induced-lesion in PC12 cells. Using fura-2/AM (acetoxymethyl ester) labelling assay, desipramine or fluoxetine at doses 1, 5 M attenuated the intracellular Ca2 overload induced by NMDA 200 M for 24h in PC12 cells. Meanwhile, using confocal microscope, it was also found that desipramine 5 M, fluoxetine 2.5 M or moclobemide 10 M decreased the NMDA 20 M induced intracellular Ca2 overload in primarily cultured rat hippocampal neurons. Furthermore, desipramine (1, 5 M), fluoxetine (1, 5 M) or moclobemide (2.5, 10 M) significantly inhibited NOS activity in NMDA (300 M) treated PC12 cells for 4h. In summary, we suggest that inhibition on the function of NMDA–Ca2 –NOS signal pathway appears to be one of the common actions for antidepressants despite their remarkably different structures, which is expected to have great implication for the evaluation and screening in vitro of new antidepressants.

Repeated exposure to chlorpyrifos alters the performance of adolescent male rats in animal models of depression and anxiety.

Chlorpyrifos (CPF) is a broad spectrum, highly effective organophosphorus (OP) pesticide that has been largely used worldwide. Over the past decades, numerous studies have assessed the potential neurotoxic effects of either acute or chronic exposure to CPF on developing brain. Despite being an acetylcholinersterase inhibitor, the effects of CPF are not only confined to cholinergic system, but are involved in a wide variety of neurotransmitter systems, especially the serotonin (5-HT) system, which leads to long-lasting changes in 5-HT-related emotional behaviors. In our present study, 4-week-old adolescent male Sprague-Dawley rats were repeatedly exposed to CPF at daily doses of 10, 20, 40, 80, and 160 mg/kg/day (s.c., 7 days), and then subjected to a battery of emotional behavioral tests that related to serotonergic function in order to determine CPF effects in adolescent rats. Results in behavioral tests demonstrated CPF significantly increased the entries to and time spent in the open arms in the elevated plus-maze test at the dose of 40-160 mg/kg, the number of shocks in the Vogels conflict test at the dose of 20-160 mg/kg, and significantly decreased the latency to feed in the novelty-suppressed feeding test in both dose range. Interestingly, in the forced swimming test, at the dose of 10mg/kg, CPF significantly increased the immobility time, whereas it significantly decreased the immobility time at the dose of 160 mg/kg. Our data suggest that repeated exposure to CPF elicits alterations of the emotional behaviors related to serotonergic nervous system in adolescent male rats. However, the underlying mechanism needs further investigations.

RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects

Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant‐like and cognition‐enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform‐specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long‐form PDE4D variants mediate antidepressant‐like and cognition‐enhancing effects, but are irrespective with emesis.

Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a severely disabling anxiety disorder that may occur following exposure to a serious traumatic event. It is a psychiatric condition that can afflict anyone who has experienced a life-threatening or violent event. Previous studies have shown that changes in 18 kDa translocator protein (TSPO) expression (or function), a promising target for treating neurological disorders without benzodiazepine-like side effects, may correlate with PTSD. However, few studies have investigated the anti-PTSD effects of TSPO ligands. AC-5216, a ligand for TSPO, induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether AC-5216 ameliorates PTSD behavior in mice. Following the training session consisting of exposure to inescapable electric foot shocks, animals were administered AC-5216 daily during the behavioral assessments, i.e., situational reminders (SRs), the open field (OF) test, the elevated plus-maze (EPM) test, and the staircase test (ST). The results indicated that exposure to foot shocks induced long-term behavioral deficiencies in the mice, including freezing and anxiety-like behavior, which were significantly ameliorated by repeated treatment with AC-5216 but without any effect on spontaneous locomotor activity or body weight. In summary, this study demonstrated the anti-PTSD effects of AC-5216 treatment, suggesting that TSPO may represent a therapeutic target for anti-PTSD drug discovery and that TSPO ligands may be a promising new class of drugs for the future treatment of PTSD.

Anxiolytic Effects of Flavonoids in Animal Models of Posttraumatic Stress Disorder

The dysregulation of the serotonergic system has long been recognized as an important factor underlying the pathophysiology of PTSD. To date, SSRIs have already been established as the firstline pharmacotherapeutic agents for treating acute and chronic PTSD. However, SSRIs largely have several disadvantages which limit their utility. Our previous study has also shown that administration of the total flavonoids, isolated from the extract of Xiaobuxin-Tang (XBXT, mild mind-easing decoction), comprising four Chinese medicines including Haematitum, Flos Inulae, Folium Phyllostachydis Henonis, and Semen Sojae Preparatum, exerted significant antidepressant-like effect in chronically mildly stressed rats, possibly mediated by serotonergic activation. Since the central serotonergic dysfunction is an important and well-known cause mediating the pathophysiology of trauma-related symptoms in PTSD, it is reasonable to predict that flavonoids may exert therapeutic effects on PTSD in animal models. Therefore, the present study aims to examine the effect of flavonoids in alleviating the enhanced anxiety and fear response induced in two PTSD animal models. Ser, an SSRI, was administered as a positive control. Furthermore, the changes of brain monoaminergic neurotransmitters after chronic flavonoids administration have also been assessed in SPS-treated rats.