• Toxicological Research
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• v.31 no.1
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• pp.49-59
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• 2015

Eye is a highly vascularised organ. There are chances that a foreign substance can enter the systemic circulation through the eye and cause oxidative stress and evoke immune response. Here the eyes of rabbits were exposed, for a period of 7 days, to 5 known ocular irritants: Cetyl pyridinium chloride (CPC), sodium salicylate (SS), imidazole (IMI), acetaminophen (ACT) and nicotinamide (NIC). The eyes were scored according to the draize scoring. Blood collected from the treated rabbit were analyzed for haematological and biochemical parameters. After sacrifice, histological analysis of the eye and analysis of pro-inflammatory biomarkers ($IL-1{\alpha}$, $IL-1{\beta}$, IL-8 and $TNF-{\alpha}$) in the cornea using ELISA was carried out. Spleen was collected and the proliferation capacities of spleenocytes were analyzed. Liver and brain were collected and assessed for oxidative stress. The eye irritation potential of the chemicals was evident from the redness and swelling of the conjunctiva and cornea. Histopathological analysis and ELISA assay showed signs of inflammation in the eye. However, the haematological and biochemical parameters showed no change. Spleenocyte proliferations showed only slight alterations which were not significant. Also oxidative stress in the brain and liver were negligible. In conclusion, chemicals which cause ocular irritation and inflammation did not show any systemic side-effects in the present scenario.

• Journal of Korean Neurosurgical Society
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• v.50 no.3
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• pp.173-178
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• 2011

Objective : The rat middle cerebral artery thread-occlusion model has been widely used to investigate the pathophysiological mechanisms of stroke and to develop therapeutic treatment. This study was conducted to analyze energy metabolism, apoptotic signal pathways, and genetic changes in the hippocampus of the ischemic rat brain. Methods : Focal transient cerebral ischemia was induced by obstructing the middle cerebral artery for two hours. After 24 hours, the induction of ischemia was confirmed by the measurement of infarct size using 2,3,5-triphenyltetrazolium chloride staining. A cDNA microarray assay was performed after isolating the hippocampus, and was used to examine changes in genetic expression patterns. Results : According to the cDNA microarray analysis, a total of 1,882 and 2,237 genes showed more than a 2-fold increase and more than a 2-fold decrease, respectively. When the genes were classified according to signal pathways, genes related with oxidative phosphorylation were found most frequently. There are several apoptotic genes that are known to be expressed during ischemic brain damage, including Akt2 and Tnfrsf1a. In this study, the expression of these genes was observed to increase by more than 2-fold. As energy metabolism related genes grew, ischemic brain damage was affected, and the expression of important genes related to apoptosis was increased/decreased.Conclusion : Our analysis revealed a significant change in the expression of energy metabolism related genes (Atp6v0d1, Atp5g2, etc.) in the hippocampus of the ischemic rat brain. Based on this data, we feel these genes have the potential to be target genes used for the development of therapeutic agents for ischemic stroke.

• Archives of Pharmacal Research
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• v.22 no.4
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• pp.361-366
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• 1999

One of the potential causes of age-related neuronal damage can be reactive oxygen species (ROS), as the brain is particularly sensitive to oxidative damage. In the present study, we investigated the effects of aging and dietary restriction (DR) on ROS generation, lipid peroxidation, and antioxidant enzymes in cerebrum, hippocampus, and cerebellum of 6-, 12-, 18-, and 24-month-old rats. ROS generation significantly increased with age in cerebrum of ad libitum (AL) rats. However, no significant age-difference was observed in hippocampus and cerebellum. DR significantly decreased ROS generation in cerebrum and cerebellum at 24-months. On the other hand, the increased lipid peroxidation of AL rats during aging was significantly reduced by DR in all regions. Our results further showed that catalase activity decreased with age in cerebellum of AL rats, which was reversed by DR, although SOD activity had little change by aging and DR in all regions. In a similar way, glutathione (GSH) peroxidase activity increased with age in cerebrum of AL rats, while DR suppressed it at 24-months. These data further support the evidence that the vulnerability to oxidative stress in the brain is region-specific.

• The Journal of the Society of Stroke on Korean Medicine
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• v.10 no.1
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• pp.8-19
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• 2009

Scutellaria Radix, originated from Scutellaria baicalensis Georgi, is one of the most important medicine in traditional Oriental medicine, and possesses anti-bacterial activity and sedative effects, can be applied in the treatment of a range of conditions including diarrhea and hepatitis. It is reported that chronic global ischemia induces neuronal damage in selective, vulnerable regions of the brain, especially the hippocampus and cerebral cortex. In the present study, to investigate the effect of Scutellaria Radix extract on cerebral disease, the changes of regional cerebral blood flow and pial arterial diameter on ischemia/reperfusion state was determinated by Laser-Doppler Flowmetry and some parameters concerned with oxidative stress also measured. When SRe were administered for five days with the concentration of 100 mg/kg, GSH activity significantly increased. But SRe administeration showed no significant change in lipid peroxidation. When the activities of CAT, Cu, Zn-SOD and GSH were measured, CAT and GSH were activated by SRe administration. When 1 and 3 ㎍/㎖ SRe was applied to the neuronal cell cultures, the quantities of LDH was significantly reduced when compared with cultures treated only with NMDA. Through this study, it can be concluded that the ischemia/reperfusion induced brain stress may have contributed to cerebral damage in rats, and the present study provides clear evidence for the beneficial effect of SRe on ischemia induced brain injury.

• Korean Journal of Food Science and Technology
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• v.30 no.5
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• pp.1222-1228
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• 1998

Stress will induce various changes in human metabolism. The remarkable phenomenon of these changes is increased energy metabolism that can induce many reactive oxygen species (ROS) production. ROS can peroxidize cellular macromolecules including lipid and protein. The object of this study was to investigate that stress may induce cellular damage by producing ROS and that Rooibos tea can protect cells against reactive oxygen species by immobilization stress in SD rat. The stress group significantly increased in 5-hydroxyindole acetic acid (5-HIAA), one of the stress hormone. Rooibos tea treatment had no effects on 5-HIAA contents, but body weight of Rooibos tea treated rat more increased than that of only the stress group. It was suggested that Rooibos tea colud not affect stress response itself, but protect against the another mechanism. We thought that the oxidative damage was caused by increased energy metabolism. Protein degradation level and lipid peroxide formation on index of oxidative damage significantly increased in the stress group. But the stress-induced activity change could not be observed in antioxidative enzymes such as superoxide dismutase, glutathione peroxidase and glutathione reductase. But the catalase activity of the brain significantly was inhibited by the stress. From these results, it was suggested that the immobilization stress induce the brain oxidative damage. However the oxidative damage was inhibited by feeding Rooibos tea containing various antioxidants, such as polyphenol, flavonoid and so on. Therefore, Rooibos tea have the protective effects against the stress caused by the ROS mediated cellular damage.

• Journal of Sasang Constitutional Medicine
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• v.11 no.2
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• pp.227-250
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• 1999

The free radical theory of aging was introduced in 1956 by Denham Harman. This aging theory proposed that normal aging results from random deleterious damage to tissues by free radical and supplying antioxidant lead to decrease oxidative damage, inhibit aging process. In this study, we investigated antioxidantive effects of four Korean constitutional prescriptions for 'Soum' constitution - Palmulgunjatang(Y1), Sipyimiguanjungtang(Y2), Osuyubujayijungtang(Y3) and Seungyangyikkibujatang(Y4). Antioxidative activity of this prescriptions was examined by 1,1-diphenyl-2-picrylhyrdazyl radicals, superoxide anion radicals, peroxyl radical, hydroxyl radical scavenging effects and erythrocyte hemolysis inhibitory effects. Y2 and Y3 were shown to have relatively high antioxidative activity on this methods. In additions, result of the cytoprotective effects of Korean constitutional prescriptions agianst 2,2'-azobis(amidinopropane) dihydrochloride (AAPH), a free radical initiator, induced cytotoxcity in human hepatoblastoma cell line was similarly obtained. On the basis of this result, we assayed the antioxidative effects of Y2 and Y3 on experimental oxidative damage, induced in mouse by 100mg/kg AAPH. Male ICR mouse were given oral administration of 500mg/kg Y2 and Y3 for 4 weeks. Thiobarbuturic acid reactive substance (TBARS) and protein degradation level in liver, plasma and brain as index of oxidative damage were decreased and thiol compound, total antioxidant status in plasma were increased by Y2 administration. But, Y3 injected group was decreased only protein degradation level in brain. Also, glutathione, a potent water-soluble endogenous antioxidant, concentration was increased by Y2 and Y3 administration in liver and brain. However, superoxide dismutase and catalase activity as a major antioxidative enzyme in vivo were not shown change by Y2 and Y3 administration. On the basis of these result, Y2 have an antioxidative effects on both water-soluble fraction and lipid-solube fraction in cell and tissues. But, Y3 has a lower antioxidative effects on lipid-soluble fraction than Y2 in cell and tissues. These results suggest that Y2 has a antioxidative effects by protect the tissue against oxygen free radical mediated oxidative damage and Y3 has a limited antioxidaitve effects on water-soluble fraction in vivo. Therefore, we make report that Y2 is more effective prescriptions for anti-aging or therapeutics of diseases.

• The Journal of Korean Medicine
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• v.26 no.1 s.61
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• pp.174-186
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• 2005

Objectives : The water extract of Samul-tang (SMT) has traditionally been used for treatment of ischemic heart and brain damage in oriental medicine. However, little is known about the mechanism by which the water extract of SMT rescues cells from these damages. Methods: This study was designed to investigate the protective mechanisms of SMT on oxidative stress-induced toxicity in H9c2 cardiomyoblast cells. Treatment with $H_2O_2$ markedly induced death of H9c2 cardiomyoblast cells in a dose-dependent manner. Results: The characteristics of H20z-induced death of H9c2 showed apparent apoptotic features such as DNA fragmentation and morphological change. However, SMT significantly reduced both H202-induced cell death and morphological change. The decrease of Bc-2 expression by High were inhibited by SMT. In addition, the increase of Bax expression was also inhibited by SMT. The cotreatment of SMT and $H_2O_2$ in H9c2 cells also induced the phosphorylation of ERK in a time-dependent manner. Moreover, PD98059, a specific inhibitor of ERK1/2 attenuated the protective effects of SMT on $H_2O_2-induced$ toxicity in H9c2 cardiomyoblast cells. These results suggest that both ERK1/2 signaling pathways play important roles in the protective effects of SMT on $H_2O_2-induced$ apoptotic death of H9c2 cells. Also, the expression profile of proteins in $H_2O_2$ cardiomyoblast cells were screened by using two-dimensional (2-D) gel electrophoresis. Among 300 spots resolved in 2-D gels, the comparison of control versus apoptosis cells revealed that signal intensity of 17 spots increased and 11 spots decreased. Conclusions: Taken together, this study suggests that the protectiw effects of the water extract of SMT against oxidative damages may be mediated by the modulation of Bc1-2 and Bax expression via the regulation of the ERK signaling pathway.

• Journal of Applied Biological Chemistry
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• v.54 no.2
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• pp.101-107
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• 2011

Aging in females is associated with a reduced metabolic function, increased incidence of neurodegenerative diseases, and cognitive dysfunction, as a result of loss in gonadal function. The change can alter the states of phosphorylation on the proteins, which cause dramatic changes in the cellular location or activity of the proteins. In this study, the differential phosphorylation of the proteins responsible for the functions related to cognition was studied using the ovariectomized adult rats. Phosphoproteomic analysis using the cerebral and hippocampal tissues could identify 51 differentially phosphorylated proteins including 12 proteins for energy metabolism, 8 cytoskeletal proteins, 6 signaling proteins, and other functional proteins in the ovariectomized rats. Further, anti-oxidative enzymes, superoxide dismutase and peroxiredoxin-2, which are known to be inactivated by phosphorylation, were found to be differentially phosphorylated in the cerebellum and hippocampus of the ovariectomized rats, respectively. Many of the deactivated proteins by differential phosphorylation identified in this study were overlapped to those of Alzheimer's disease cases. These results will provide information for neurodegenerative learning and memory impairments in women as brought about by menopause.

• Journal of the Korean Society of Food Science and Nutrition
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• v.39 no.4
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• pp.506-510
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• 2010

As an attempt to develop new functional health beverage by using medicinal herb, we investigated the effect of medicinal plant extract (MPE) on mean arterial blood pressure (MABP) and regional cerebral blood flow (rCBF) of rats. The changes of MABP and rCBF were determined by LDF methods. LDF allows for real time, noninvasive, continuous recordings of local CBF. MABP in MPE treated rats showed significant change of MPE 1.0 and 10.0 mg/kg. MPE i.v. administration showed significant increase of rCBF in a dose-dependent manner. Propranolol pretreated MABP showed significant change in the increase of MPE. rCBF of propranolol pretreated rats showed significant change from the i.v. injection concentration of 1.0 and 10.0 mg/kg. The ischemia/reperfusion induced oxidative stress may have contributed to cerebral damage in rats, and the present study provides clear evidence for the beneficial effect of MPE on ischemia induced brain injury. Also, the action mechanism in elevation effect of MPE on rCBF might be concerned with the role of $\beta$-adrenoceptor. The exact component and mechanism remains for the future study.

• Toxicological Research
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• v.30 no.4
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• pp.267-276
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• 2014

Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that these behavioral changes could be associated with altered dopaminergic neurotransmission, providing a therapeutic basis for psychiatric disorders caused by Pb toxicity.