• The Korean Journal of Physiology and Pharmacology
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• 제20권4호
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• pp.357-366
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• 2016

Pro-inflammatory cytokine and brain-derived neurotrophic factor (BDNF) are modulated in post-traumatic stress disorder (PTSD). This study investigated the effects of ibuprofen (IBU) on enhanced anxiety in a rat model of PTSD induced by a single prolonged stress (SPS) procedure. The effects of IBU on inflammation and BDNF modulation in the hippocampus and the mechanisms underlying for anxiolytic action of IBU were also investigated. Male Sprague-Dawley rats were given IBU (20 or 40 mg/kg, i.p., once daily) for 14 days. Daily IBU (40 mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index in the EPM test, and increased the time spent in the center of an open field after SPS. IBU administration significantly decreased the expression of pro-inflammatory mediators, such as tumor necrosis $factor-{\alpha}$, $interleukin-1{\beta}$, and BDNF, in the hippocampus, as assessed by reverse transcription-polymerase chain reaction analysis and immunohistochemistry. These findings suggest that IBU exerts a therapeutic effect on PTSD that might be at least partially mediated by alleviation of anxiety symptoms due to its anti-inflammatory activity and BDNF expression in the rat brain.

• Journal of Microbiology and Biotechnology
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• 제22권5호
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• pp.708-720
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• 2012

In this study, we assessed the effects of ginsenoside Re (GRe) administration on repeated immobilization stress-induced behavioral alterations using the forced swimming test (FST), the elevated plus maze (EPM), and the active avoidance conditioning test (AAT). Additionally, we examined the effect of GRe on the central adrenergic system by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity and brain-derived neurotrophic factor (BDNF) mRNA expression in the rat brain. Male rats received 10, 20, or 50 mg/kg GRe (i.p.) 30 min before daily exposures to repeated immobilization stress (2 h/day) for 10 days. Activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to repeated immobilization was confirmed by measuring serum levels of corticosterone (CORT) and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Repeated immobilization stress increased immobility in the FST and reduced open-arm exploration in the EPM test. It also increased the probability of escape failures in the AAT test, indicating a reduced avoidance response. Daily administration of GRe during the repeated immobilization stress period significantly inhibited the stress-induced behavioral deficits in these behavioral tests. Administration of GRe also significantly blocked the increase in TH expression in the locus coeruleus (LC) and the decrease in BDNF mRNA expression in the hippocampus. Taken together, these findings indicate that administration of GRe prior to immobilization stress significantly improved helpless behaviors and cognitive impairment, possibly through modulating the central noradrenergic system in rats. These findings suggest that GRe may be a useful agent for treating complex symptoms of depression, anxiety, and cognitive impairment.

• Journal of Microbiology and Biotechnology
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• 제22권3호
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• pp.422-430
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• 2012

Previous studies have demonstrated that repeated restraint stress in rodents produces increases in depression and anxiety-like behaviors and alters the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. The current study focused on the impact of Bupleurum falcatum (BF) extract administration on repeated restraint stress-induced behavioral responses using the forced swimming test (FST) and elevated plus maze (EPM) test. Immunohistochemical examinations of tyrosine hydroxylase (TH) expression in rat brain were also conducted. Male rats received daily doses of 20, 50, or 100 mg/kg (i.p.) BF extract for 15 days, 30 min prior to restraint stress (4 h/day). Hypothalamic-pituitary-adrenal axis activation in response to repeated restraint stress was confirmed base on serum corticosterone levels and CRF expression in the hypothalamus. Animals that were pre-treated with BF extract displayed significantly reduced immobility in the FST and increased open-arm exploration in the EPM test in comparison with controls. BF also blocked the increase in TH expression in the locus coeruleus of treated rats that experienced restraint stress. Together, these results demonstrate that BF extract administration prior to restraint stress significantly reduces depression and anxiety-like behaviors, possibly through central adrenergic mechanisms, and they suggest a role for BF extract in the treatment of depression and anxiety disorders.

• 약학회지
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• 제51권3호
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• pp.219-227
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• 2007

Ginsenoside Rgl (Rgl), the pharmacologically active constituent of ginseng (Panax ginseng C.A. Meyer), has a variety of biological activities. The present study was undertaken to evaluate a possibility of Rgl whether it can be used in treatment or prevention of stress disorders. Animals were stressed by immobilization for 2 hours or electroshocks for 20 minutes. The normal group was not exposed to any stress. Rgl was subcutaneously injected as dosages of 5 and 10 mg/kg and red ginseng (RG) was orally administered 200 mg/kg as the positive control. Animals were given supplements for 5 days without stress, and then were given supplements for 5 days with stress. We recorded stress-related behavioral changes of experimental animals using the Etho-vision system. Weight of adrenal gland and levels of corticosterone in plasma were measured and stress related behaviors (smelling, grooming, face washing, rearing) were observed. Rgl didn't make significant behavioral changes in total open field and elevated plus maze test. Rgl did not influence on behavioral changes induced by electroshock stress. Whereas, 10 mg/kg of Rgl alleviated the increment of the freezing and face washing time and the decrement of the smelling and rearing time induced by restraint stress. The administration of Rgl 10 mg/kg has significantly increased the endurance time on rotating rod and swimming pool tests compared to the control group. These results indicate that Rgl can alleviate the damage induced by physical stress. This result suggests that Rgl may bea new candidate for treating stress related disorder.

• Biomolecules & Therapeutics
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• 제20권4호
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• pp.418-424
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• 2012

Repeated stress induces corticosterone release. However, it is not clear that stress results in further elevation of corticosterone levels, and the roles of released corticosterone to aggravate stress-related symptoms are also not clear. This study investigated whether neuronal modulation was induced in the amygdala after two kinds of stress, that is, such as electric shock and corticosterone injection. It was found that stress by electric shock decreased the expression of tyrosine hydoroxylase (TH) in the amygdala while the expression of pERK was increased. However, there is no difference in the expressions of TH and pERK in the frontal cortex compared with those of the control group. The level of corticosterone was significantly increased in the serum after stress. To determine the effect of corticosterone on the induction of anxiety and the expression of TH, the rats received corticosterone (20 mg or 40 mg/kg i.p.) for 1 day, 1 week, 2 weeks and 3 weeks, respectively. The spent time in open arms of the EPM (elevated plus maze) test was significantly decreased after 1 week, 2 weeks and 3 weeks. The time spent in open arms of the EPM test after repeated injections of corticosterone was significantly decreased in a dose-dependent manner. The expression of TH in the amygdala was reduced after following repeated corticosterone treatment for 2 weeks and 3 weeks. Collectively, this study suggests that corticosterone has a major role in the induction of anxiety and the modulation of TH expression, at least, in the amygdala.

• Journal of Ginseng Research
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• 제45권6호
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• pp.706-716
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• 2021

Background: Irritable bowel syndrome (IBS), the most common functional gastrointestinal disorder, is characterized by chronic abdominal pain and bowel habit changes. Although diverse complicated etiologies are involved in its pathogenesis, a dysregulated gut-brain axis may be an important factor. Red ginseng (RG), a traditional herbal medicine, is proven to have anti-inflammatory effects and improve brain function; however, these effects have not been investigated in IBS. Methods: Three-day intracolonic zymosan injections were used to induce post-infectious human IBS-like symptoms in mice. The animals were randomized to receive either phosphate-buffered saline (CG) or RG (30/100/300 mg/kg) for 10 days. Amitriptyline and sulfasalazine were used as positive controls. Macroscopic scoring was performed on day 4. Visceral pain and anxiety-like behaviors were assessed by colorectal distension and elevated plus maze and open field tests, respectively, on day 10. Next-generation sequencing of gut microbiota was performed, and biomarkers involved in gut-brain axis responses were analyzed. Results: Compared to CG, RG significantly decreased the macroscopic score, frequency of visceral pain, and anxiety-like behavior in the IBS mice. These effects were comparable to those after sulfasalazine and amitriptyline treatments. Moreover, RG significantly increased the proliferation of beneficial microbes, including Lactobacillus johnsonii, Lactobacillus reuteri, and Parabacteroides goldsteinii. RG significantly suppressed expression of IL-1β and c-fos in the gut and prefrontal cortex, respectively. Further, it restored the plasma levels of corticosterone to within the normal range, accompanied by an increase in adrenocorticotropic hormone. Conclusion: RG may be a potential therapeutic option for the management of human IBS.

• Journal of Ginseng Research
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• 제45권2호
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• pp.254-263
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• 2021

Background: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. Methods: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. Results: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. Conclusion: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

• The Korean Journal of Pain
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• 제35권2호
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• pp.173-182
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• 2022

Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

• Journal of Ginseng Research
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• 제46권6호
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• pp.819-829
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• 2022

Background: Anxiolytic properties of Korean Red Ginseng (KRG) have been previously reported. However, the exact mechanism(s) of action remains to be elucidated. The present study investigated the effect of KRG on immobilization-induced anxiety-like behaviors in mice and explored the involvement of the serotonin and GABA systems and BDNF in the anxiolytic action. Methods: Mice were orally administered with KRG (200 mg/kg/day) for 4 weeks and immobilized once daily for 2 h. p-Chlorophenylalanine (p-CPA) was intraperitoneally injected on day 22-28, and flumazenil or bicuculline was injected on day 25-28. After behavioral evaluations, brains were dissected for biochemical analyses. Results: KRG improved immobilization-induced anxiety-like behaviors in mice, as assessed by the elevated plus maze (EPM) and marble burying tests (MBT). The anxiolytic effect of KRG was comparable to that of fluoxetine, a reference drug clinically used for anxiety disorders. A serotonin synthesis inhibitor, p-CPA, blocked the effect of KRG in the EPM and MBT, indicating the requirement of serotonin synthesis for anxiolytic action. In addition, the anxiolytic effect of KRG was inhibited by bicuculline (a GABA_A antagonist) in MBT, implying the involvement of GABA transmission. Western blotting analyses revealed that KRG upregulated the expression of tryptophan hydroxylase and GABA_A receptor in the brain, which was blocked by p-CPA. Enhanced BDNF expression by KRG in the hippocampus was also indicated to mediate the anxiolytic action of KRG in immobilized mice. Conclusion: KRG exhibited the anxiolytic effect in immobilized mice by multiple mechanisms of action, involving enhanced serotonin and GABA transmissions and BDNF expression.

• The Korean Journal of Physiology and Pharmacology
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• 제27권1호
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• pp.113-125
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• 2023

It has been reported that stressful events in early life influence behavior in adulthood and are associated with different psychiatric disorders, such as major depression, post-traumatic stress disorder, bipolar disorder, and anxiety disorder. Maternal separation (MS) is a representative animal model for reproducing childhood stress. It is used as an animal model for depression, and has well-known effects, such as increasing anxiety behavior and causing abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis. This study investigated the effect of MS on anxiety or aggression-like behavior and the number of GABAergic neurons in the hippocampus. Mice were separated from their dams for four hours per day for 19 d from postnatal day two. Elevated plus maze (EPM) test, resident-intruder (RI) test, and counted glutamic acid decarboxylase 67 (GAD67) or parvalbumin (PV) positive cells in the hippocampus were executed using immunohistochemistry. The maternal segregation group exhibited increased anxiety and aggression in the EPM test and the RI test. GAD67-positive neurons were increased in the hippocampal regions we observed: dentate gyrus (DG), CA3, CA1, subiculum, presubiculum, and parasubiculum. PV-positive neurons were increased in the DG, CA3, presubiculum, and parasubiculum. Consistent with behavioral changes, corticosterone was increased in the MS group, suggesting that the behavioral changes induced by MS were expressed through the effect on the HPA axis. Altogether, MS alters anxiety and aggression levels, possibly through alteration of cytoarchitecture and output of the ventral hippocampus that induces the dysfunction of the HPA axis.