Z-Guggulsterone Produces Antidepressant-Like Effects in Mice through Activation of the BDNF Signaling Pathway.

Background: Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression. Methods: The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone. Results: Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone. Conclusions: Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis.

Antidepressant-Like Effects of GM1 Ganglioside Involving the BDNF Signaling Cascade in Mice.

BACKGROUND: Depression is a serious psychiatric disorder that easily causes physical impairments and a high suicide rate. Monosialotetrahexosylganglioside is a crucial ganglioside for the central nervous system and has been reported to affect the function of the brain derived neurotrophic factor system. This study is aimed to evaluate whether monosialotetrahexosylganglioside has antidepressant-like effects. METHODS: Antidepressant-like effects of monosialotetrahexosylganglioside were assessed in the chronic social defeat stress model of depression, and various behavioral tests were performed. Changes in the brain derived neurotrophic factor signaling pathway after chronic social defeat stress and monosialotetrahexosylganglioside treatment were also investigated. A tryptophan hydroxylase inhibitor and brain derived neurotrophic factor signaling inhibitors were used to determine the antidepressant mechanisms of monosialotetrahexosylganglioside. RESULTS: Monosialotetrahexosylganglioside administration significantly reversed the chronic social defeat stress-induced reduction of sucrose preference and social interaction in mice and also prevented the increased immobility time in the forced swim test and tail suspension test. In addition, monosialotetrahexosylganglioside completely ameliorated the stress-induced dysfunction of brain derived neurotrophic factor signaling cascade in the hippocampus and medial prefrontal cortex, 2 regions closely involved in the pathophysiology of depression. Furthermore, the usage of brain derived neurotrophic factor signaling cascade inhibitors, K252a and anti-brain derived neurotrophic factor antibody, each abolished the antidepressant-like effects of monosialotetrahexosylganglioside, while the usage of a serotonin system inhibitor did not. CONCLUSIONS: Taken together, our findings suggest that monosialotetrahexosylganglioside indeed has antidepressant-like effects, and these effects were mediated through the activation of brain derived neurotrophic factor signaling cascade.

Tetramethylpyrazine Produces Antidepressant-Like Effects in Mice Through Promotion of BDNF Signaling Pathway.

BACKGROUND: Current antidepressants are clinically effective only after several weeks of administration. Tetramethylpyrazine (TMP) is an identified component of Ligusticum wallichii with neuroprotective effects. Here, we investigated the antidepressant effects of TMP in mice models of depression. METHODS: Antidepressant effects of TMP were first detected in the forced swim test (FST) and tail suspension test (TST), and further assessed in the chronic social defeat stress (CSDS) model. Changes in the brain-derived neurotrophic factor (BDNF) signaling pathway and in hippocampal neurogenesis after CSDS and TMP treatment were then investigated. A tryptophan hydroxylase inhibitor and BDNF signaling inhibitors were also used to determine the mechanisms of TMP. RESULTS: TMP exhibited potent antidepressant effects in the FST and TST without affecting locomotor activity. TMP also prevented the CSDS-induced symptoms. Moreover, TMP completely restored the CSDS-induced decrease of BDNF signaling pathway and hippocampal neurogenesis. Furthermore, a blockade of the BDNF signaling pathway prevented the antidepressant effects of TMP, while TMP produced no influence on the monoaminergic system. CONCLUSIONS: In conclusion, these data provide the first evidence that TMP has antidepressant effects, and this was mediated by promoting the BDNF signaling pathway.

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway.

RATIONALE: Current anti-depressants are clinically effective only after several weeks of administration and always produce side effects. OBJECTIVES: WY14643 is a selective agonist of peroxisome proliferator-activated receptor-α with neuroprotective and neurotrophic effects. Here, we investigated the anti-depressant effects of WY14643 in mice models of depression. METHODS: We assessed the anti-depressant effects of WY14643 in the forced swim test (FST), tail suspension test (TST) and chronic social defeat stress (CSDS) model. Western blotting and immunohistochemistry studies were further performed to detect the effects of WY14643 on the brain-derived neurotrophic factor (BDNF) signaling pathway and hippocampal neurogenesis. The anti-BDNF antibody, BDNF signaling inhibitor, and tryptophan hydroxylase inhibitor were also used to explore the anti-depressant mechanisms of WY14643. RESULTS: WY14643 exhibited robust anti-depressant effects in the FST and TST and also protected against the CSDS stress in mice models. Moreover, WY14643 reversed the stress-induced elevation of corticosterone, deficiency of BDNF signaling pathway, and hippocampal neurogenesis. Blockade of BDNF signaling cascade, not the monoaminergic system, abolished all the anti-depressant effects of WY14643. CONCLUSIONS: These data provide the first evidence that WY14643 exerts anti-depressant-like activity through promoting the BDNF signaling pathway.

Rescue of cardiac failing and remodelling by inhibition of protein phosphatase 1γ is associated with suppression of the alternative splicing factor-mediated splicing of Ca2+/calmodulin-dependent protein kinase δ.

Our previous studies showed that protein phosphatase 1γ (PP1γ) exacerbates cardiomyocyte apoptosis through promotion of Ca(2+)/calmodulin-dependent protein kinase δ (CaMKIIδ) splicing. Here we determine the role of PP1γ in abdominal aorta constriction-induced hypertrophy and remodelling in rat hearts. Systolic blood pressure and echocardiographic measurements were used to evaluate the model of cardiac hypertrophy. Sirius red staining and invasive haemodynamic/cardiac index measurements were used to evaluate the effects of PP1γ or inhibitor 1 of PP1 transfection. Western blot, reverse transcription polymerase chain reaction and co-immunoprecipitation were applied to investigate the molecular mechanisms. Transfection of PP1γ increased the value of the heart mass index, left ventricular mass index and cardiac fibrosis, and simultaneously decreased the value of maximal left ventricular pressure increase and decline rate, ejection fraction, fractional shortening, and left ventricular end-diastolic pressure, as well as left ventricular systolic pressure. Transfection of inhibitor 1 of PP1, however, showed opposite effects on the aforementioned indexes. Overexpression of PP1γ potentiated CaMKIIδC production and decreased CaMKIIδB production in the hypertrophic heart. In contrast, inhibition of PP1γ re-balanced the CaMKIIδ splicing. Furthermore, CaMKII activity was found to be augmented or attenuated by PP1γ overexpression or inhibition, respectively. Further mechanistic studies showed that abdominal aorta constriction stress specifically increased the association of alternative splicing factor with PP1γ, but not with PP1ß. Overexpression of PP1γ, but not inhibitor 1 of PP1, further potentiated this association. These results suggest that PP1γ alters the cardiac hypertrophy and remodelling likely through promotion of the alternative splicing factor-mediated splicing of CaMKIIδ.