• The Korean Journal of Pain
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• v.33 no.3
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• pp.216-225
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• 2020

Background: Garlic oil is a rich source of organosulfur compounds including diallyl disulfide and diallyl trisulfide. There have been studies showing the neuroprotective actions of these organosulfur compounds. However, the potential of these organosulfur compounds in neuropathic pain has not been explored. The present study was aimed at investigating the pain attenuating potential of diallyl disulfide and diallyl trisulfide in chronic constriction injury (CCI)-induced neuropathic pain in rats. The study also explored their pain-attenuating mechanisms through modulation of H₂S, brain-derived neurotrophin factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf2). Methods: The rats were subjected to CCI injury by ligating the sciatic nerve in four places. The development of neuropathic pain was measured by assessing mechanical hyperalgesia (Randall-Selittotest), mechanical allodynia (Von Frey test), and cold allodynia (acetone drop test) on 14th day after surgery. Results: Administration of diallyl disulfide (25 and 50 mg/kg) and diallyl trisulfide (20 and 40 mg/kg) for 14 days led to a significant reduction in pain in CCI-subjected rats. Moreover, treatment with these organosulfur compounds led to the restoration of H₂S, BDNF and Nrf2 levels in the sciatic nerve and dorsal root ganglia. Co-administration of ANA-12 (BDNF blocker) abolished pain attenuating actions as well as BDNF and the Nrf2 restorative actions of diallyl disulfide and diallyl trisulfide, without modulating H₂S levels. Conclusions: Diallyl disulfide and diallyl trisulfide have the potential to attenuate neuropathic pain in CCI-subjected rats possibly through activation of H₂S-BDNF-Nrf2 signaling pathway.

• Journal of the Korean Applied Science and Technology
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• v.36 no.3
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• pp.876-884
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• 2019

We investigated the effect of moderate- and high-intensity resistance training on hippocampal neurotrophic factors and peripheral CCL11 levels in high-fat diet (HFD)-induced obese mice. C57/black male mice received a 4 weeks diet of normal (control, CON; n = 9) or a high-fat diet (HF; n = 27) to induce obesity. Thereafter, the HF group was subdivided equally into the HF, HF + moderate-intensity exercise (HFME), and HF + high-intensity exercise (HFHE) groups (n = 9, respectively), and mice were subjected to ladder-climbing exercise for 8 weeks. The hippocampal brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels were significantly lower in the HF group than in the CON group (p < 0.05). In addition, in the HFME and HFHE groups were significantly higher than in the HF group (p < 0.05). The peripheral CCL11 levels were significantly higher in the HF group than in the CON group (p < 0.05). In addition, in the HFME and HFHE groups were significantly lower than in the HF group (p < 0.05). However, there was no significant difference according to the exercise intensity among the groups. Collectively, these results suggest that obesity can induce down-regulation of neurotrophic factors and inhibition of neurogenesis. In contrast, regardless of exercise intensity, resistance training may have a positive effect on improving brain function by inducing increased expression of neurotrophic factors.

• Journal of Korean Neurosurgical Society
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• v.62 no.6
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• pp.626-634
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• 2019

Objective : Nerve growth factor (NGF) is a member of the neurotrophic factor family and plays a vital role in the physiological processes of organisms, especially in the nervous system. Many recent studies have reported that NGF is also involved in the regulation of tumourigenesis by either promoting or suppressing tumor growth, which depends on the location and type of tumor. However, little is known regarding the effect of NGF on interspinal schwannoma (IS). In the present study, we aimed to explored whether mouse nerve growth factor (mNGF), which is widely used in the clinic, can influence the growth of interspinal schwannoma cells (ISCs) isolated from IS in vitro. Methods : ISCs were isolated, cultured and identified by S-100 with immunofluorescence analysis. S-100-positive cells were divided into five groups, and separately cultured with various concentrations of mNGF (0 [phosphate buffered saline, PBS], 40, 80, 160, and 320 ng/mL) for 24 hours. Western blot and quantantive real time polymerase chain reaction (PCR) were applied to detect tyrosine kinase A (TrkA) receptor and p75 neurotrophin receptor ($p75^{NTR}$) in each group. Crystal violet staining was selected to assess the effect of mNGF (160 ng/mL) on ISCs growth. Results : ISCs growth was enhanced by mNGF in a dose-dependent manner. The result of crystal violet staining revealed that it was significantly strengthened the cells growth kinetics when cultured with 160 ng/mL mNGF compared to PBS group. Western blot and quantantive real time PCR discovered that TrkA receptor and mRNA expression were both up-regualated under the condition of mNGF, expecially in 160 ng/mL, while the exoression of $p75^{NTR}$ demonstrated no difference among groups. Conclusion : From these data, we conclude that exogenous mNGF can facilitate ISC growth by activating both TrkA receptor and $p75^{NTR}$. In addition, patients who are suffering from IS should not be administered mNGF in the clinic.

• Development and Reproduction
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• v.12 no.1
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• pp.1-8
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• 2008

Specific protocols to increase the differentiation of neuronal cells from embryonic stem (ES) cells have been well established, such as retinoic acid induction and lineage selection of neuronal cells. For the neuropathological studies, ES-derived neurons (ES neurons) must show normal physiological characteristics related to cell death and survival and should be maintained in vitro for a sufficient time to show insults-specific cell death without spontaneous death. When mouse ES cells were plated onto astrocytes monolayer after retinoic acid induction, most ES cells differentiated into neuronal cells, which were confirmed by the presence of specific neuronal markers, and the cultures were viable for at least four weeks. When these cultures were examined for vulnerability to glutamate excitotoxicity, ES neurons were vulnerable to excitotoxic insults mediated by agonist-specific receptors. The vulnerability to excitotoxic death increased with developmental age of ES neurons in vitro. Specific receptors for Neurotrophin and GDNF family ligands were present in ES neurons. GDNF and NT-3 could modulate the survival and excitotoxic vulnerability of ES neurons. The vulnerability and resistance to toxic insults, which are essential requirements of model culture systems for neuropathological studies, make ES neurons to a useful model culture system. Especially ES cell are highly amenable to genetic modification unlikely to primary neuronal cells, which will give us a chance to answer more complicated neurophysiological questions. Recently there was an outstanding attempt to explore the cellular toxicity using human ES cells (Schrattenholz & Klemm, 2007) and it suggested that ES cells could be a new model system for neurophysiological studies soon and go further a large-scale screening system for pharmacological compounds in the future.

• Korean Journal of Biological Psychiatry
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• v.12 no.2
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• pp.189-195
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• 2005

Objects:Some studies have suggested that brain-derived neurotrophic factor(BDNF), one of the most important neurotrophins, is involved in pathophysiology of depression and suicide. This study was performed to determine whether there is an abnormality in plasma BDNF concentration in suicidal attempters. Methods:The subjects were 71 suicidal attempters who visited emergency rooms in multi-medical centers. All subjects had been interviewed by using Structured Clinical Interview for DSM-IV(SCID), Hamilton Depression Rating Scale(HDRS), Young Mania Rating Scale(YMRS), and Positive And Negative Syndrome Scale(PANSS). The severity of the suicidal behavior was measured by Lethality of Suicide Attempt Rating Scale(LSARS) and Risk-Rescue Rating(RRR) system. Seventy-one age, sex, and diagnosis matched non-suicidal psychiatric patients who were consecutively admitted to a psychiatric ward during the same period recruited as psychiatric controls. They were drug-naive or drug-free at least more than 2 months. In addition, 80 healthy controls were randomly selected as normal controls. Plasma BDNF level was measured by the enzyme linked immunosorbent assay(ELISA) methods. Results:In overall F-test, differences of the plasma BDNF levels among the groups were statistically significant(F=20.226, p<0.001). In the multiple comparisons(Scheffe), while mean levels of plasma BDNF between normal controls and non-suicidal psychiatric patients were similar(p=0.984), the BDNF levels of suicidal attempters were lower than those of other two groups(p<0.001). LSARS and RRR did not reveal any significant correlations with BDNF levels in suicidal attempters. Conclusion:These results suggest that reduction of plasma BDNF level is related to suicidal behavior and BDNF level may be a biological marker of suicidal behavior.

• Molecules and Cells
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• v.38 no.3
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• pp.221-228
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• 2015

Because Schwann cells perform the triple tasks of myelination, axon guidance and neurotrophin synthesis, they are candidates for cell transplantation that might cure some types of nervous-system degenerative diseases or injuries. However, Schwann cells are difficult to obtain. As another option, ectomesenchymal stem cells (EMSCs) can be easily harvested from the nasal respiratory mucosa. Whether fibrin, an important transplantation vehicle, can improve the differentiation of EMSCs into Schwann-like cells (SLCs) deserves further research. EMSCs were isolated from rat nasal respiratory mucosa and were purified using anti-CD133 magnetic cell sorting. The purified cells strongly expressed HNK-1, nestin, $p75^{NTR}$, S-100, and vimentin. Using nuclear staining, the MTT assay and Western blotting analysis of the expression of cell-cycle markers, the proliferation rate of EMSCs on a fibrin matrix was found to be significantly higher than that of cells grown on a plastic surface but insignificantly lower than that of cells grown on fibronectin. Additionally, the EMSCs grown on the fibrin matrix expressed myelination-related molecules, including myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and galactocerebrosides (GalCer), more strongly than did those grown on fibronectin or a plastic surface. Furthermore, the EMSCs grown on the fibrin matrix synthesized more neurotrophins compared with those grown on fibronectin or a plastic surface. The expression level of integrin in EMSCs grown on fibrin was similar to that of cells grown on fibronectin but was higher than that of cells grown on a plastic surface. These results demonstrated that fibrin not only promoted EMSC proliferation but also the differentiation of EMSCs into the SLCs. Our findings suggested that fibrin has great promise as a cell transplantation vehicle for the treatment of some types of nervous system diseases or injuries.

• Biomolecules & Therapeutics
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• v.20 no.1
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• pp.27-35
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• 2012

Oroxylin A is a flavone isolated from a medicinal herb reported to be effective in reducing the inflammatory and oxidative stresses. It also modulates the production of brain derived neurotrophic factor (BDNF) in cortical neurons by the transactivation of cAMP response element-binding protein (CREB). As a neurotrophin, BDNF plays roles in neuronal development, differentiation, synaptogenesis, and neural protection from the harmful stimuli. Adenosine $A2_A$ receptor colocalized with BDNF in brain and the functional interaction between $A2_A$ receptor stimulation and BDNF action has been suggested. In this study, we investigated the possibility that oroxylin A modulates BDNF production in cortical neuron through the regulation of $A2_A$ receptor system. As expected, CGS21680 ($A2_A$ receptor agonist) induced BDNF expression and release, however, an antagonist, ZM241385, prevented oroxylin A-induced increase in BDNF production. Oroxylin A activated the PI3K-Akt-GSK-$3{\beta}$ signaling pathway, which is inhibited by ZM241385 and the blockade of the signaling pathway abolished the increase in BDNF production. The physiological roles of oroxylin A-induced BDNF production were demonstrated by the increased neurite extension as well as synapse formation from neurons. Overall, oroxylin A might regulate BDNF production in cortical neuron through $A2_A$ receptor stimulation, which promotes cellular survival, synapse formation and neurite extension.

• Journal of Life Science
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• v.21 no.7
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• pp.985-991
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• 2011

The purpose of this study was to investigate the biological effect of obesity-induced oxidative damage on neurogenesis and early protein expression. Obesity was induced I thirty 4-week old male Sprague-Dawley rats through a high fat diet for 15 weeks. After one week of environmental adaptation, the rats were divided into 2 groups: high fat diet sedentary group (HDS, n=15) and high fat diet training group (HDT, n=15). Exercise training was performed 5 times a week for 8 weeks, with mild-intensity treadmill running for weeks 1-4 and moderate-intensity treadmill running for weeks 5-8. After the 8 week training period, we analyzed lipid profiles, serum 8-hydroxyguanosine (8-OHdG), liver tissue malondialdehyde (MDA) related to oxidative damage factors, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), c-fos, c-jun, and extracellular signal regulated kinase (Erk) in the hippocampus. The results of this study are as follows. There were differences between HDS and HDT in triglyceride (TG) and total cholesterol (TC) (p<0.05). In high density lipoprotein (HDL-c), the HDT was higher than HDS after treadmill training (p<0.05). In 8-OHdG, the HDT was lower than HDS after treadmill training (p<0.05). Genetic expressions of c-jun, BDNF and MDA in the HDT were higher than in the HDS after treadmill training in hippocampus (p<0.05). Therefore, we conclude that 8 weeks of treadmill training can improve imbalanced lipid profiles, reduce oxidative damage, and activate neurogenesis in obese rats.

• Journal of Ginseng Research
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• v.28 no.2
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• pp.94-103
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• 2004

Korean red ginseng is known to have anti-stress and memory enhancing effects. Recent studies suggested that stress-induced inhibition of adult neurogenesis in hippocampus may contribute, in part, to decreased negative feedback inhibition of HPA axis. In order to elucidate the mechanism of Korean red ginseng in anti-stress and memory enhancing effects, we observed the effects of repeated treatment of Korean red ginseng total saponin (GTS, 50 mg/kg, i.p.) in response to repeated unpredictable stress for 10 days. Male Sprague-Dawley rats (230 - 260 g) received with either GTS (50 mg/kg, i.p.) or vehicle (1 ml/kg, i.p.) 1 h before stress for 10 days. Rats were injected with bromodeoxyuridine (BrdU, 50 mg/kg, i.p.) 16-18 he after last stress procedure, and were sacrificed 2 hr later by perfusion. Immunohistochemistry of BrdU was done to measure proliferation of neural progenitor cells in hippocampus, which was used as an index of neurogenesis. Repeated GTS treatment for 10 days increased neurogenesis in subgranular zone area of dentate gyrus (SGZ), but not hilus, compared with vehicle-treated rats. Repeated unpredictable stress did not affect the neurogenesis compared with controls, while repeated GTS treatment increased neurogenesis in SGZ in repeated unpredictable stress-exposed group. BDNF mRNA was also measured in subregions of hippocampus by in situ hybridization. BDNF mRNA expression in CA3 and CA1 pyramidal cell layer was increased by repeated GTS treatment but not in dentate granule cell layer. Repeated unpredictable stresses significantly decreased BDNF mRNA expression in all subregions of hippocampus, but repeated GTS treatment did not prevent stress-induced BDNF mRNA downregulation. Given that repeated GTS treatment increased proliferation of neural progenitor cells in repeated unpredictable stress-exposed rats in the presence of decreased BDNF mRNA expression in dentate granule cell layer, it raise the possibility that BDNF may not playa significant role in GTS-mediated increase of neurogenesis in adult rat hippocampus. Also, these results suggest that repeated GTS treatment increased neurogenesis of SGZ and BDNF mRNA expression, which may account for memory enhancing effect of Korean red ginseng. In addition, repeated GTS treatment appears not to have anti-stress effects in terms of neurotrophin, but GTS-mediated increase of neurogenesis in hippocampus may contribute to increase negative feedback inhibition of HPA axis.