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This study aims to reveal the potential relationship between 5-HT and oxidative stress in the organism. Our in vitro experiments in RIN-14B cells showed that anoxia leads the cells to the state of oxidative stress. Administration of exogenous 5-HT exacerbated this effect, whereas the inhibition of Tph1, LP533401 alleviated the oxidative stress. Several research articles reported that Cinnabar (consists of more than 96% mercury sulfide, HgS), which is widely used in both Chinese and Indian traditional medicine prescriptions, has been involved in the regulation of 5-HT. The present research revealed that HgS relieved the level of oxidative stress of RIN-14B cells. This pharmacological activity was also observed in the prescription drug Zuotai, in which HgS accounts for 54.5%, and these effects were found to be similar to LP533401, an experimental drug to treat pulmonary hypertension. Further, our in vivo experiments revealed that the administration of cinnabar or prescription drug Zuotai in zebrafish reduced the reactive oxygen species (ROS) induced by hypoxia and cured behavioral abnormalities. Taken together, in organisms with hypoxia induced oxidative stress 5-HT levels were found to be abnormally elevated, indicating that 5-HT could regulate oxidative stress, and the decrease in the 5-HT levels, behavioral abnormalities after treatment with cinnabar and Zuotai, we may conclude that the therapeutic and pharmacologic effect of cinnabar and Zuotai may be based on the regulation of 5-HT metabolism and relief of oxidative stress. Even though they aren't toxic at the present dosage in both cell lines and zebrafish, their dose dependent toxicities are yet to be evaluated.
Recent evidence has established that consumption of High-fat diet (HFD)-induced obesity is associated with deficits in hippocampus-dependent memory/learning and mood states. Nevertheless the link between obesity and emotional disorders still remains to be elucidated. This issue is of particular interest during adolescence, which is important period for shaping learning/memory and mood regulation that can be sensitive to the detrimental effects of HFD. Our present study is focused to investigate behavioral and metabolic influences of short-term HFD intake in adolescent C57BL/6 mice. HFD caused weight gain, impaired glucose tolerance (IGT) and depression-like behavior as early as after 3 weeks which was clearly proved by a decrease in number of groomings in the open field test (OFT) and an increase in immobility time in the tail suspension test (TST). In the 4th week HFD induced obese model was fully developed and above behavioral symptoms were more dominant (decrease in number of crossings and groomings and increase in immobility time in both FST and TST). At the end of 6th week hippocampal analysis revealed the differences in morphology (reduced Nissl positive neurons and decreased the 5-HT1A receptor expression), neuronal survival (increased cleaved caspase-3 expression), synaptic plasticity (down regulation of p-CREB and BDNF), and inflammatory responses (increase in expression of pro-inflammatory cytokines and decrease in expression of anti-inflammatory cyokines) in HFD mice. Our results demonstrate that, high-fat feeding of adolescent mice could provoke "depression-like" behavior as early as 3 weeks and modulate structure, neuron survival and neuroinflammation in hippocampus as early as 6 weeks proving that adolescent age is much prone to adverse effects of HFD, which causes obesity, behavioral differences, memory and learning deficiencies.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with a broad spectrum of liver injury. Oxidant stress is believed to be the pathogenesis of NAFLD as the "second hit". Hydrogen peroxide is widely used as an oxidant reagent to induce the oxidant injury of cells and larval zebrafish. Recently, cichoric acid is being studied extensively for its obesity attenuating, hepatic steatosis reduction and anti-oxidant effects. In this study, to identify whether CRA could protect the H2O2 induced oxidant injury via anti-oxidant impact by using L02 and HepG2 hepatocytes as in vitro and larval zebrafish as in vivo injury models, and evaluated the protective and anti-oxidant effects of CRA by pretreated it on both in vitro and in vivo models. CRA was found to reduce the production of ROS and MDA, activate the anti-oxidant enzymes SOD and GSH-px, and pathways Keap1-Nrf2 and HO-1. These results demonstrated that CRA might protect the liver injury by its anti-oxidant effect, which could be a potential therapeutic agent of NAFLD.
Recent literature reported the adverse effects of high-fat diet (HFD) on animal's emotional and cognitive function. An HFD-induced obesity/hyperlipidemia is accompanied by hormonal and neurochemical changes that can lead to depression. The important roles of gut-derived serotonin (5-Hydroxytryptamine, 5-HT) during this processing have been increasingly focused. Hence, to determine the potential role of gut-derived serotonin, HFD model was established in C57BL/6 mice. At the 4th week of feeding, a pharmacologic inhibitor of gut-derived 5-HT synthesis LP533401 (12.5 mg/kg/day), simvastatin (SIM) (5 mg/kg/day) and benzafibrate (BZ) (75 mg/kg/day) were administered for two weeks by oral gavage. Then, intraperitoneal glucose tolerance test (IPGTT), open field test (OFT), tail suspension test (TST), forced swim test (FST), sucrose preference test (SPT) were used to evaluate metabolic and neurobehavioral performances. Immunohistochemical staining, real-time quantitative PCR and other methods were to explore possible mechanisms. It was found that HFD feeding and drug treatments had some significant effects on neurobehaviors and brain: (1) All administrations reduced the total cholesterol (TC) and triglyceride (TG) parametric abnormality caused by HFD. LP533401 and SIM could significantly improve the impaired glucose tolerance, while BZ had no significant effect. (2) LP533401, SIM and BZ alleviated depression-like behavior of HFD mice in OFT, TST, FST and SPT. (3) LP533401 and SIM reversed the inhibition of Tryptophan Hydroxylase 2, Tph2 gene expression and the activation of Indoleamine 2,3-dioxy-Genase, IDO expression in HFD-treated brain, whereas BZ did not. (4) LP533401, SIM and BZ restored the inhibitory expression of 5-HT1A receptor in HFD hippocampus. Conclusions: Selective inhibition of intestinal 5-HT can attenuate depressive-like behavior, reduce 5-HT1AR impairment in hippocampus and correct abnormal 5-HT pathway in brain while ameliorating HFD-induced glucose intolerance. Further experiments are warranted to define the adequate strategy of targeting peripheral 5-HT for the treatment of such co-morbidity.
BACKGROUND: A high-fat diet (HFD)-induced obesity/hyperlipidemia is accompanied by hormonal and neurochemical changes that can be associated with depression. Emerging studies indicate that simvastatin (SMV, decreasing cholesterol levels) has therapeutic effects on neurological and neuropsychiatric diseases through hippocampal-dependent function. However, the studies on the HFD exposure in adolescent animals, which investigate the neuroprotective effects of SMV on the hippocampal morphology, serotonin (5-HT) system and inflammation, are limited. Hence, the aim of this study was to determine whether SMV attenuates HFD-induced major depressive disorders in adolescent animals and, more specifically, acts as an anti-neuroinflammatory response. METHODS: Twenty-four male C57BL/6 mice were fed a control (n = 8), HFD (n = 8) and HFD + SMV (n = 8) for 14 weeks. In HFD + SMV group, SMV (10 mg/kg) was administrated from the 10th week of HFD feeding. The open field test (OFT) and the tail suspension test (TST) were used to examine the effect of SMV on behavioral performance. HE and Nissl staining were conducted to detect hippocampal morphology and neural survival. Expression of the inflammatory cytokine genes was assayed by quantitative polymerase chain reaction (Q-PCR). RESULTS: Firstly, alterations in lipid parameters were minimized after SMV treatment. HFD-induced depression-like behavior, which was evidenced by an increase in immobility time in TST along with considerable decrease in locomotion activity, was significantly attenuated by SMV therapy for 4 weeks. Additionally, SMV could reduce HFD-induced structural abnormality, neuronal injury, serotonergic system disturbance and pro-inflammatory cytokine over-expression in the hippocampus. Neuroimmunological changes in central hippocampus displayed a similar characteristic (only IL-1β, IL-6, TNF-α) with that in periphery spleen, whereas they appeared in an entirely opposite trend with that in cerebral cortex. CONCLUSION: Our results suggest that SMV may be a promising treatment for HFD-induced depression-like behavior during adolescent period through brain region-specific neuroninflammatory mechanisms.