Bin-Bin Liu

Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus.

BDNF signaling is necessary for the antidepressant-like effect of naringenin.

Previous studies in our laboratory have demonstrated that naringenin produced antidepressant-like action in tail suspension test (TST). However, the underlying mechanisms involved in neurotrophin system by which naringenin works have not been investigated. The present study extends earlier works on the role of brain-derived neurotrophic factor (BDNF) in regulating the antidepressant-like actions of naringenin in chronic unpredictable mild stress (CUMS). We showed that a 21-day regimen with naringenin reversed the decreased sucrose preference in sucrose preference test (SPT) and the prolonged first feeding latency in novelty-suppressed feeding test (NSFT), without affecting home-cage feeding consumption. In addition, we also found that naringenin promoted BDNF expression in the hippocampus but not in the frontal cortex in both non-stressed and CUMS mice. Moreover, the antidepressant-like effect of naringenin in SPT and NSFT induced by naringenin administration were totally abolished by K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB). In conclusion, our findings suggest that the antidepressant-like effect of naringenin may be mediated, at least in part, by the activation of BDNF signaling in the hippocampus.

Essential oil of Perilla frutescens-induced change in hippocampal expression of brain-derived neurotrophic factor in chronic unpredictable mild stress in mice.

ETHNOPHARMACOLOGICAL RELEVANCE Perilla frutescens (Perilla leaf), a traditional Chinese medicinal herb, has been used for centuries to treat various conditions including depression. A previous study of the authors demonstrated that essential oil of Perilla frutescens (EOPF) attenuated the depressive-like behavior in mice. AIM OF THE STUDY This study was undertaken to explore the dynamic change of behaviors and brain-derived neurotrophic factor (BDNF) expression induced by chronic unpredictable mild stress (CUMS), and improved by EOPF. MATERIALS AND METHODS Four separate CUMS experimental groups (1-week, 2-week, 3-week and 4-week treatment) were treated with EOPF (3 mg/kg and 6 mg/kg, p.o.) or fluoxetine (20 mg/kg, p.o.), followed by sucrose preference, locomotor activity, immobility and hippocampal BDNF measurement. RESULTS EOPF, as well as fluoxetine, restored the CUMS-induced decreased sucrose preference and increased immobility time, without affecting body weight gain and locomotor activity. Furthermore, CUMS (3 or 4-week) produced a reduction in both BDNF mRNA and protein expression in the hippocampus, which were ameliorated by EOPF (4-week) and fluoxetine (3 or 4-week) treatment. CONCLUSION These results presented here show that BDNF is expressed depending on length of CUMS procedure and EOPF administration. And this study might contribute to the underlying reason for the slow onset of antidepressant activity in clinic.

Nobiletin Ameliorates the Deficits in Hippocampal BDNF, TrkB, and Synapsin I Induced by Chronic Unpredictable Mild Stress

Background. Our previous study has demonstrated that nobiletin could reverse the behavioral alterations in stressed mice. However, the relation of its antidepressant-like action with neurotrophic molecular expression remains unknown. This study aimed to explore the antidepressant-like mechanism of nobiletin related to the neurotrophic system in rats exposed to chronic unpredictable mild stress (CUMS). Methods. Depressive-like anhedonia (assessed by sucrose preference) and serum corticosterone secretion were evaluated in the CUMS, followed by brain-derived neurotrophic factor (BDNF), its tropomyosin-related kinase receptor B (TrkB), and the downstream target synapsin I expressions in the hippocampus. Results. Anhedonia, which occurred within week 2, was rapidly ameliorated by nobiletin. While fluoxetine needed additional 2 weeks to improve the anhedonia. In addition, nobiletin administration for 5 weeks significantly ameliorated CUMS-induced increase in serum corticosterone levels. Furthermore, we also found that CUMS-induced deficits of hippocampal BDNF, TrkB, and synapsin I were ameliorated by nobiletin. Conclusions. Taken together, these findings suggest that nobiletin produces rapidly acting antidepressant-like responses in the CUMS and imply that BDNF-TrkB pathway may play an important role in the antidepressant-like effect of nobiletin.

Ethanol extracts from Hemerocallis citrina attenuate the upregulation of proinflammatory cytokines and indoleamine 2,3-dioxygenase in rats

ETHNOPHARMACOLOGICAL RELEVANCE Hemerocallis citrina, a traditional herbal medicine, has been used for the improvement of behavioral and emotional status in Eastern-Asia countries. Previous studies in our laboratory demonstrated that ethanol extracts from Hemerocallis citrina (HCE) enhanced monoamines and brain-derived neurotrophic factor (BDNF) in depression-like model of rodents. MATERIALS AND METHODS The present study extends earlier works on the role of anti-inflammation in regulating the antidepressant-like actions of HCE in rats exposed to chronic unpredictable mild stress (CUMS). Frontal cortex and hippocampal proinflammatory cytokines levels and indoleamine 2,3-dioxygenase (IDO) activity were measured after 4-week HCE treatment in the CUMS an control rats. RESULTS Chronic administration of HCE reversed the decreased sucrose preference in sucrose preference test. In addition, we also found that HCE inhibited interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression, as well as IDO activity in frontal cortex and hippocampus, which were increased in rats exposed to CUMS. CONCLUSIONS Combining with our previous studies, our present finding suggests that the anti-inflammatory property of HCE might play a crucial role in its antidepressant-like effect through, at least in part, the restoration or improvement of monoaminergic and neurotrophin systems.

Hippocampal BDNF signaling restored with chronic asiaticoside treatment in depression-like mice

Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of depression in the brain. Recently, increasing studies have focused on the antidepressant-like mechanism of BDNF and its downstream signaling pathway. A previous study has shown that asiaticoside produced an antidepressant-like action in the mouse tail suspension test and forced swimming test. However, the neurotrophic mechanism that is affected by asiaticoside is unclear. Our present study aimed to verify whether asiaticoside produces an antidepressant-like effect through the activation of BDNF signaling in chronic unpredictable mild stress (CUMS). The results showed that mice treated with asiaticoside for four weeks reversed the decreased sucrose preference and increased immobility time that was observed in CUMS mice. In addition, we found that asiaticoside up-regulated BDNF, PSD-95 and synapsin I expression only in the hippocampus but not in the frontal cortex in both non-stressed and CUMS mice. However, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), completely abolished the antidepressant-like effect of asiaticoside. Moreover, the expression of hippocampal BDNF, PSD-95 and synapsin I that had increased with asiaticoside also declined with K252a pretreatment. In conclusion, our study implies that it is possible that asiaticoside exerts its antidepressant-like action by activating BDNF signaling in the hippocampus.

Essential oil of Syzygium aromaticum reverses the deficits of stress-induced behaviors and hippocampal p-ERK/p-CREB/brain-derived neurotrophic factor expression.

Syzygium aromaticum has been widely used in traditional medicine. Our study investigated the safety and antidepressant-like effects of the essential oil of S. aromaticum after acute or long-term treatment. Using GC-MS, a total of eight volatile constituents were identified in the essential oil of S. aromaticum. The single LD50 was approximately 4500 mg/kg based on a 24-h acute oral toxicity study. In a long-term repeated toxicity study of this essential oil (100, 200, and 400 mg/kg, p. o.), only 400 mg/kg induced a significant decrease in body weight. In addition, no significant changes in relative organ weights and histopathological analysis were observed in all doses of essential oil-treated mice compared with the control group. Furthermore, acute S. aromaticum essential oil administration by gavage exerted antidepressant-like effects in the forced swimming test (200 mg/kg, p < 0.05) and tail suspension test (100 and 200 mg/kg, p < 0.05). Long-term S. aromaticum essential oil treatment via gavage significantly increased sucrose preference (50 mg/kg, p < 0.05; 100 and 200 mg/kg, p < 0.01) as well as elevated the protein levels of hippocampal p-ERK, p-CREB, and brain-derived neurotrophic factor in mice exposed to chronic unpredictable mild stress. These results confirmed the safety of the essential oil of S. aromaticum and suggested that its potent antidepressant-like property might be attributed to the improvement in the hippocampal pERK1/2-pCREB-BDNF pathway in rats exposed to chronic unpredictable mild stress.

Activation of hippocampal BDNF signaling is involved in the antidepressant-like effect of the NMDA receptor antagonist 7-chlorokynurenic acid.

Previous studies showed that acute 7-chlorokynurenic acid treatment produced a rapid antidepressant-like action in depression-like animal models. However, the underlying mechanism involved in neurotrophin system about 7-chlorokynurenic acid is unclear. Our present study aimed to verify whether chronic 7-chlorokynurenic acid treatment produced an antidepressant-like effect through the activation of brain-derived neurotrophic factor (BDNF) signaling in mice exposed to chronic unpredictable mild stress (CUMS). In addition, we performed an oral toxicological evaluation of chronic 7-chlorokynurenic acid administration in mice. The results showed that a two-week administration with 7-chlorokynurenic acid reversed the decreased sucrose preference and prolonged first feeding latency. In addition, 7-chlorokynurenic acid significantly reversed the CUMS-induced down-regulation of BDNF, p-ERK, p-Akt, PSD-95, synapsin I and cell proliferation in the hippocampus. In contrast, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), blocked the antidepressant-like effect and the improvement of 7-chlorokynurenic acid. Furthermore, we found that 7-chlorokynurenic acid did not produce any toxicological effect in mice. In conclusion, our findings suggest that the antidepressant-like effect of 7-chlorokynurenic acid may be mediated, at least in part, by activating BDNF signaling in the hippocampus.

Screening of the antidepressant-like effect of the traditional Chinese medicinal formula Si-Ni-San and their possible mechanism of action in mice

Background: The traditional Chinese medicine formula Si-Ni-San has well therapeutic applications in improvement of mental diseases including depression. However, the neuropharmacological and neuroendocrine mechanisms of the formula on antidepressant-like action have not been reported. Objective: Herein, we explored the antidepressant-like effect and its mechanism of Si-Ni-San. Materials and Methods: Acute effect of Si-Ni-San on the immobility time was assessed in the mouse forced swim test (FST) and tail suspension test (TST). Moreover, we investigated the neurochemical, neuroendocrine, and neurotrophin systems involved in the antidepressant-like effect of this formula. Results: Si-Ni-San significantly decreased the immobility time after acute treatment in the mouse TST (1300 mg/kg) but not in the FST compared with the control group. In addition, pretreatment of mice with PCPA or AMPT prevented the anti-immobility effect of Si-Ni-San (1300 mg/kg) in the TST. Moreover, acute Si-Ni-San (1300 mg/kg) decreased serum corticosterone levels, elevated serotonin (5-HT), norepinephrine (NE), and dopamine (DA) levels without affecting brain-derived neurotrophic factor (BDNF) levels in the whole brain exposed to TST. Conclusion: The acute antidepressant-like action of Si-Ni-San is mediated by the monoaminergic and neuroendocrine systems although underlying mechanism still remains to be further elucidated, and this formula should be further investigated as an alternative therapeutic approach for the treatment of depression.