• Journal of Ginseng Research
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• 제44권4호
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• pp.593-602
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• 2020

Background: Heat stress orchestrates neurodegenerative disorders and results in the formation of reactive oxygen species that leads to cell death. Although the immunomodulatory effects of ginseng are well studied, the mechanism by which ginseng alleviates heat stress in the brain remains elusive. Methods: Rats were exposed to intermittent heat stress for 6 months, and brain samples were examined to elucidate survival and antiinflammatory effect after Korean Red Ginseng (KRG) treatment. Results: Intermittent long-term heat stress (ILTHS) upregulated the expression of cyclooxygenase 2 and inducible nitric oxide synthase, increasing infiltration of inflammatory cells (hematoxylin and eosin staining) and the level of proinflammatory cytokines [tumor necrosis factor α, interferon gamma (IFN-γ), interleukin (IL)-1β, IL-6], leading to cell death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) and elevated markers of oxidative stress damage (myeloperoxidase and malondialdehyde), resulting in the downregulation of antiapoptotic markers (Bcl-2 and Bcl-x_L) and expression of estrogen receptor beta and brain-derived neurotrophic factor, key factors in regulating neuronal cell survival. In contrast, KRG mitigated ILTHS-induced release of proinflammatory mediators, upregulated the mRNA level of the antiinflammatory cytokine IL-10, and increased myeloperoxidase and malondialdehyde levels. In addition, KRG significantly decreased the expression of the proapoptotic marker (Bax), did not affect caspase-3 expression, but increased the expression of antiapoptotic markers (Bcl-2 and Bcl-x_L). Furthermore, KRG significantly activated the expression of both estrogen receptor beta and brain-derived neurotrophic factor. Conclusion: ILTHS induced oxidative stress responses and inflammatory molecules, which can lead to impaired neurogenesis and ultimately neuronal death, whereas, KRG, being the antioxidant, inhibited neuronal damage and increased cell viability.

• The Korean Journal of Physiology and Pharmacology
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• 제8권1호
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• pp.1-5
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• 2004

Transient forebrain ischemia results in the delayed neuronal death in the CA1 area of the hippo-campus. The present study was performed to determine effects of aminoguanidine, a selective iNOS inhibitor, on the generation of peroxynitrite and delayed neuronal death occurring in the hippocampus following transient forebrain ischemia. Transient forebrain ischemia was produced in the conscious rats by four-vessel occlusion for 10 min. Treatment with aminoguanidine (100 mg/kg or 200 mg/kg, i.p.) or saline (0.4 ml/100 g, i.p.) was started 30 min following ischemia-reperfusion and the animals were then injected twice daily until 12 h before sacrifice. Immunohistochemical method was used to detect 3-nitrotyrosine, a marker of peroxynitrite production. Posttreatment of aminoguanidine (200 mg/kg) significantly attenuated the neuronal death in the hippocampal CA1 area 3 days, but not 7 days, after ischemia-reperfusion. 3-Nitrotyrosine immunoreactivity was enhanced in the hippocampal CA1 area 3 days after reperfusion, which was prevented by the treatment of aminoguanidine (100 mg/kg and 200 mg/kg). Our findings showed that (1) the generation of peroxynitrite in the hippocampal CA1 area 3 days after ischemia-reperfusion was dependent on the iNOS activity; (2) the postischemic delayed neuronal death was attenuated in the early phase through the prevention of peroxynitrite generation by an iNOS inhibitor.

• The Korean Journal of Physiology and Pharmacology
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• 제16권6호
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• pp.423-429
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• 2012

Brain ischemia leads to overstimulation of N-methyl-D-aspartate (NMDA) receptors, referred as excitotoxicity, which mediates neuronal cell death. However, less attention has been paid to changes in synaptic activity and morphology that could have an important impact on cell function and survival following ischemic insult. In this study, we investigated the effects of reperfusion after oxygen/glucose deprivation (OGD) not only upon neuronal cell death, but also on ultrastructural and biochemical characteristics of postsynaptic density (PSD) protein, in the stratum lucidum of the CA3 area in organotypic hippocampal slice cultures. After OGD/reperfusion, neurons were found to be damaged; the organelles such as mitochondria, endoplasmic reticulum, dendrites, and synaptic terminals were swollen; and the PSD became thicker and irregular. Ethanolic phosphotungstic acid staining showed that the density of PSD was significantly decreased, and the thickness and length of the PSD were significantly increased in the OGD/reperfusion group compared to the control. The levels of PSD proteins, including PSD-95, NMDA receptor 1, NMDA receptor 2B, and calcium/calmodulin-dependent protein kinase II, were significantly decreased following OGD/reperfusion. These results suggest that OGD/reperfusion induces significant modifications to PSDs in the CA3 area of organotypic hippocampal slice cultures, both morphologically and biochemically, and this may contribute to neuronal cell death and synaptic dysfunction after OGD/reperfusion.

• 한국식품영양학회지
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• 제31권6호
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• pp.865-872
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• 2018

In neuronal cell deaths, oxidative stress is normally implicated with a most of these deaths occurring in neurodegenerative disorders such as the Alzheimer's and Parkinson's diseases. In this study, the neuroprotective effects of Schisandra chinensis (SC) and Ribes fasciculatum (RF) extracts on hydrogen peroxide ($H_2O_2$)-induced oxidative stress in neuroblastic cell line were investigated. For an hour, hydrogen peroxide of $100{\mu}M$ concentration, was induced on neuroblastic cells, causing apoptic cell death. For the neuroprotection, a sample of neuroblastic cells had been pre-treated with SC and RF extracts for 24 hours before application of the hydrogen peroxide. No neurotoxic effects were observed in the cells that had been treated by SC and RF. This prove that the treatment of SC and RF extract prevented apoptotic cell death of neuroblastic cell line exposed to oxidative injury. In addition, applying both SC and RF extracts at a 7:3 ratio increased the neuronal cell survival rate, compared to individual treatments of SC and RF extract. This study suggests that SC and RF extracts may be potential therapeutic agents for the prevention of neuronal cell death.

• 대한약리학회지
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• 제32권2호
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• pp.169-175
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• 1996

The reactivity of the sulfhydryl (thiol) group of homocysteine has been associated with an Increased risk of atherosclerosis, thrombosis and stroke. Thiols also react with nitric oxide (NO, an endothelium-derived relaxing factor (EDRF) ), forming S-nitrosothiols that have been reported to have potent vasodilatory and antiplatelet effects and been expected to decrease adverse vascular effects of homocysteine. The present study was aimed to Investigate whether the S-nitrosation of homocysteine modulates the neurotoxic effects of homocysteine. An 18 hour-exposure of cultured rat cortical neurons to homocysteine ( >1 mM) resulted in a significant neuronal cell death. At comparable concentrations ( <10 mM), however, S-nitrosohomocysteine did not induce neuronal cell death. Furthermore, S-nitrosohomocysteirle partially blocked NMDA-mediated neurotoxicity. S-nitrosohomocysteine also decreased NMDA-mediated increases in intracellular calcium concentration. The present data indicate that in brain nitric oxide produced from neuronal and nonneuronal cells can modulate the potential, adverse properties of homocysteine.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.94.3-95
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• 2003

Familial form of Alzheimer's disease (FAD) is caused by mutations in presenilin-l (PS-1) and presenilin-2 (PS-2). PS1 and PS2 mutation are known to similar effects on the production of amyloid peptide (A ) and cause of neuronal cell dath in the brain of patient of Alzheimer's disease. The importance of the alternation of cellular calcium homeostasis in the neuronal cell death by PS1 mutation in a variety of experimental systems has been demonstrated. However, no studies on the effect of PS2 of mutant PS2 on cellular calcium homeostasis, and relevance of its change to neuronal cell vulnerability against neurotoxins have been reported. (omitted)

• Molecules and Cells
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• 제26권1호
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• pp.12-17
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• 2008

The TrkA tyrosine kinase is activated by autophosphorylation in response to NGF, and plays an important role in cell survival, differentiation, and apoptosis. To investigate its role in cell fate determination, we produced stable TrkA-inducible SK-N-MC and U2OS cell lines using the Tet-On system. Interestingly, TrkA overexpression induced substantial cell death even in the absence of NGF, by stimulating ERK phosphorylation and caspase-7 activation leading to PARP cleavage. TrkA-mediated cell death was shown by the annexin-V binding assay to be, at least in part, apoptotic in both SK-N-MC and U2OS cells. Furthermore, the truncated form (p18) of Bax accumulated in the TrkA-induced cells, suggesting that TrkA induces mitochondria-mediated apoptosis. NGF treatment augmented the cell death induced by TrkA overexpression. This TrkA-induced cell death was blocked by the tyrosine kinase inhibitors, K-252a and GW441756. Moreover, TrkA overexpression inhibited long-term proliferation of both the neuronal SK-N-MC cells and the non-neuronal U2OS cells, suggesting a potential role of TrkA as a tumor suppressor.

• 동의생리병리학회지
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• 제19권3호
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• pp.647-655
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• 2005

This study demonstrated anti-oxidative and neuroprotective effects of Rhei Rhizoma. Anti-oxidative effects were studied on BV-2 microglia cells damaged by $H_2O_2$ and nitric oxide. Neuroprotective effects were studied by using oxygen/glucose deprivation of the organotypic hippocampal slice cultures. The results obtained are as follows; The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of neuronal cell death area and cell death area percentages in CA1 region of ischemic damaged hippocampus cultures during whole 48 hours of the experiment. The group treated with 50 mg/ml of Puerariae Radix demonstrated decreases of neuronal cell death area and cell death area percentages in CA1 region, but these were not significant statistically. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of neuronal cell death area and cell death area percentages in dentate gyrus of ischemic damaged hippocampus cultures during whole 48 hours of the experiment. The group treated with 50 mg/ml of Puerariae Radix demonstrated decreases of neuronal cell death area and cell death area percentages in dentate gyrus, but these were not significant statistically. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of TUNEL-positive cells in both CA1 region and dentate gyrus of ischemic damaged hippocampus cultures. The group treated with 50 mg/ml of Puerariae Radix demonstrated significant decrease of TUNEL-positive cells in CA1 region, but not in dentate gyrus of ischemic damaged hippocampus. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of LDH concentrations in culture media of ischemic damaged hippocampus cultures. The group treated with 50 mg/ml of Puerariae Radix demonstrated decrease of LDH concentrations in culture media, but it was not significant statistically. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant increases of cell viabilities of BV-2 microglia cells damaged by $H_2O_2$. The group treated with 50 mg/ml of Puerariae Radix demonstrated increase of cell viability of BV-2 microglia cells, but it was not significant statistically. The group treated with 0.5 mg/ml of Puerariae Radix revealed significant increase of cell viability of BV-2 microglia cells damaged by nitric oxide. The groups treated with 5 and 50 mg/ml of Puerariae Radix demonstrated increases of cell viabilities of BV-2 microglia cells, but these were not significant statistically. These results suggested that Puerariae Radix revealed neuroprotective effects through the control effect of apoptosis and oxidative damages.

• 약학회지
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• 제44권1호
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• pp.29-35
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• 2000

The methanol extracts were prepared from 46 oriental medicines currently used for stroke treatment, and the effects were assessed on the excitotoxic neuronal cell death induced by L-glutamate(Glu) in primary cultured rat cortical neurons. The extracts from Angelicae gigantis Radix, Manitis Squama, Acori graminei Rhizoma, Uncariae Ramulus et Uncus, Alpiniae Fructus, Paeoniae Radix, and Cnidii Rhizoma inhibited the Glu-induced neurotoxicity with the IC$_50$ values of 95.2, 218.6, 263.3, 295.1, 297.9, 310.1, and 446.7 $\mu$g/ m$\ell$, respectively. The extracts from Arisaematis Rhizoma, Loranthi Ramulus, Anemarrhenae Rhizoma, Carthami Flos, Clematidis Radix, Bambusae Concretio Silicea, and Angelicae koreanae Radix also exhibited significant inhibition of the toxicity. In contrast, the extracts from Aconiti Tuber Araliae cordatae Radix, Curcumae Rhizoma, Leonuri Herba, Polygalae Radix, Salviae Radix, and Siegesbeckiae Herba increased the Glu-induced toxicity at the concentrations of 500 and 1000 $\mu$g/m$\ell$. Rest of the extracts evaluated in the present study showed minor or negligible inhibition. liken together the oriental medicines including Angelicae gigantis Radix, Muitis Squama, Acori graminei Rhizoma, Uncariae Ramulus et Uncus, and Alpiniae Fructus appear to exert pharmacological effects through the inhibition of excitotoxic neuronal cell death. Further studies are in progress to characterize active principles in these extracts.

• 대한임상검사과학회지
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• 제47권1호
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• pp.51-58
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• 2015

Ethanol has long been implicated in triggering apoptotic neurodegeneration. Alcohol also may indirectly harm the fetus by imparing the mother's physiology. We examined the effects of ethanol on immature brain of mice. Three-weeks-old female ICR strain mice daily intraperitoneally injected with ethanol at the concentration of 4 and 20% in saline for 0, 6, and 24 hours and 1 and 4 weeks. The mice were weighted and sacrificed, and the brains were ectomized for the present histological, immunohistochemical and TUNEL assays. Based on the histologic hematoxylin and eosin stain, immunohistochemical expression of glutamate receptor protein and neuronal cell adhesion molecule (NCAM) were evaluated. The cerebral cortex of the ethanol-treated group showed few typical symptoms of apoptosis such as chromosome condensation and disintegration of the cell bodies. TUNEL staining revealed DNA fragmentation in the 6 and 24 hours. This results demonstrated that acute ethanol administration causes neuronal cell death. I found that either glutamate receptor inhibition or activation could induce cerebellar degeneration as ethanol effect. Neuronal death also can be induced by excess activity of certain neurotransmitter, including glutamate. Neurons must establish cell-to-cell contact during growth and development in order to survive, migrate to their final destination, and develop appropriate connections with neighboring cell. Purkinje cell in cerebellar are especially vulnerable to the cell death and degeneration. After ethanol treatment in cerebellar, NCAM had decreased by 4 weeks. This result suggest that apoptosis seems to be involved in the slow elimination of neuron and cerebellar degeneration.