Li-Tao Yi

Involvement of monoaminergic system in the antidepressant-like effect of the flavonoid naringenin in mice

Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. In this study, the neuropharmacological mechanism of the dietary flavonoid naringenin was investigated in the mouse behavioral models of depression. For this purpose, we investigated the influence of pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester or α-methyl-p-tyrosine, respectively in the anti-immobility effect of naringenin. Compared to the control group, naringenin significantly decreased the immobility time after acute treatment in the mouse tail suspension test (10, 20 and 50 mg/kg), but not in the forced swimming test, without producing locomotor alteration in the open-field test. In addition, pretreatment of mice with p-chlorophenylalanine methyl ester (100 mg/kg) or α-methyl-p-tyrosine (100 mg/kg) prevented the anti-immobility effect of naringenin (20 mg/kg) in the tail suspension test. Taken together, this data demonstrated that naringenin possessed potent antidepressant-like property via the central serotonergic and noradrenergic systems. Thus, our findings suggest the therapeutic potential of this dietary flavonoid in central nervous system disorders especially depression where monoaminergic systems are involved.

Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin.

Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant-like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1mg/kg, s.c., a serotonin 5-HT(1A) receptor antagonist), cyproheptadine (3mg/kg, i.p., a serotonin 5-HT(2) receptor antagonist), prazosin (62.5μg/kg, i.p., an α(1)-adrenoceptor antagonist), SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist) or propranolol (5mg/kg, i.p., a β-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression.

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.

Chronic treatment with baicalin prevents the chronic mild stress-induced depressive-like behavior: involving the inhibition of cyclooxygenase-2 in rat brain.

Baicalin, a major constituent of flavonoids isolated from Scutellariae Radix, has been previously confirmed to decrease the duration of immobility in mice exposed to the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms are still seldom studied in chronic mild stress (CMS) model of depression. In the present study, we attempted to investigate the effects of baicalin on the depressive-like behavior, the mRNA expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E(2) (PGE(2)) levels in the frontal cortex and hippocampus. Moreover, the serum corticosterone levels were also examined. We found that CMS procedure not only decreased the sucrose preference and increased serum corticosterone levels, but also elevated the activity and mRNA expression of COX-2, and increased PGE(2) levels in rat brain regions. Treatment with baicalin (10, 20, 40 mg/kg) prevented these abnormalities induced by CMS. These results confirmed that baicalin exerted antidepressant-like effects, and suggested its mechanisms at least partially related to decease COX-2 activity and expression, subsequently resulted in reduction of PGE(2) levels in brain. Our findings may provide a new aspect to understand the antidepressant action of baicalin, which is targeted on the COX-2 system in brain.

Ethanol extracts from Hemerocallis citrina attenuate the decreases of brain-derived neurotrophic factor, TrkB levels in rat induced by corticosterone administration.

ETHNOPHARMACOLOGICAL RELEVANCE Hemerocallis citrina, a traditional herbal medicine, has been used for the improvement of behavioral and emotional status in Eastern-Asia countries. AIM OF THE STUDY Our previous studies have demonstrated that the ethanol extracts of H. citrina flowers (HCE) reversed the behavioral alterations and monoamine neurotransmitter dysfunctions in stressed mice. However, the relation of its antidepressant-like action with neurotrophic molecular expressions remains unknown. MATERIALS AND METHODS To clarify this, we explored the effect of HCE (32.5, 65, 130mg/kg, p.o.) on the behavior, brain-derived neurotrophic factor (BDNF) and its receptor (TrkB) in depression-like rats induced by exogenous administration of the stress hormone corticosterone (40mg/kg, s.c.). RESULTS It was observed that repeated administration of corticosterone induced an elevation on the serum corticosterone levels, which caused the abnormalities observed in the sucrose preference test and forced swimming test (FST). Administration of HCE (65 and 130mg/kg) reversed the changes above and up-regulated the BDNF and TrkB receptor protein expressions in the brain region of frontal cortex and hippocampus. CONCLUSION These findings confirm that HCE produce an antidepressant-like effect in corticosterone-induced depression-like model of rats and this effect is at least partly mediated by BDNF-TrkB signaling in the frontal cortex and 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.

Antidepressant-like behavioral, neurochemical and neuroendocrine effects of naringenin in the mouse repeated tail suspension test.

Our previous study demonstrated that the citrus bioflavonoid naringenin ameliorated behavioral alterations via the central serotonergic and noradrenergic systems in the tail suspension test (TST) induced mice. To better understand its pharmacological activity, mice were submitted to three 6min-TSTs one week apart (Day 1: test, Day 7: retest 1, Day 14: retest 2) followed by hippocampal glucocorticoid receptor (GR), monoamine neurotransmitters and serum corticosterone measurement. The results suggested that repeated TST detected the gradual increase in the efficacy of naringenin over time, additionally 1-day (20 mg/kg), 7-day (10, 20 mg/kg) and 14-day (5, 10, 20 mg/kg) naringenin treatment markedly decreased the immobility time. Moreover, administration of naringenin for 14 days (20 mg/kg) increased hippocampal serotonin (5-HT), norepinephrine (NE) and GR levels, and reduced serum corticosterone levels in mice exposed to the repeated TST. Overall, the present study indicated that the re-exposure would facilitate the detection of the anti-immobility effects of antidepressant drugs in the mouse TST, and clearly demonstrated that the antidepressant-like effect of naringenin may be mediated by an interaction with neuroendocrine and neurochemical systems.

Antihyperglycemic activity of Anoectochilus roxburghii polysaccharose in diabetic mice induced by high-fat diet and streptozotocin

ETHNOPHARMACOLOGICAL RELEVANCE Anoectochilus roxburghii is a traditional Chinese herb used for treatment of diabetes and some other diseases. Anoectochilus roxburghii polysaccharose (ARP) is the main constituent of Anoectochilus roxburghii. The present study aimed to investigate the antidiabetic effects of ARP in diabetic mice induced by high-fat diet and streptozotocin. MATERIALS AND METHODS Two doses of ARP (100 or 300 mg/kg) were administered once daily for 25 days to diabetic mice. To evaluate the antidiabetic effects of ARP, the fasting glucose levels, aspartate aminotransferase (AST), alanine transaminase (ALT) and superoxide dismutase (SOD) activities, malondialdehyde (MDA) content, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and liver glycogen were examined. Furthermore, histological examinations were carried out on the separated pancreas and liver of mice. RESULTS Compared with untreated diabetic mice, ARP (100 or 300 mg/kg) caused a significant decrease in blood glucose levels, activities of AST and ALT, and MDA contents, and a significant increase in liver glycogen contents, SOD activities, thymus index and spleen index. Simultaneously, the alteration in lipid metabolism was partially attenuated as evidenced by decreased serum TC, TG and LDL-C concentrations in diabetic mice. In addition, histological examinations showed that administration of ARP (100 or 300 mg/kg) significantly attenuated the pathologic lesions in pancreas and liver of diabetic mice, and improved pancreas and liver function. CONCLUSIONS The antidiabetic activity of ARP may be attributed to the improvement of glucose and lipid metabolism, increase of immune protection and reduction of oxidative stress.

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.