• The Korean Journal of Pain
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• v.22 no.3
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• pp.199-205
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• 2009

Background: A major ingredient of green tea is epigallocatechin-3-gallate (EGCG), and this is known to have many beneficial effects for cancer prevention and also on the cardiovascular system and neurodegenerative diseases through its anti-oxidant, anti-angiogenic, anti-inflammatory, lipid-lowering and neuroprotective properties. Its actions on nociception and the spinal nervous system have been examined in only a few studies, and in these studies EGCG showed an antinociceptive effect on inflammatory and neuropathic pain, and a neuroprotective effect in motor neuron disease. This study was performed to investigate the effect of EGCG on acute thermal pain and the development of morphine tolerance at the spinal level. Methods: The experimental subjects were male Sprague-Dawley rats and the Hot-Box test was employed. A single or double-lumen intrathecal catheter was implanted at the lumbar enlargement for drug administration. An osmotic pump was used to infuse morphine for 7 days for induction of morphine tolerance. EGCG was injected repeatedly for 7 days at twice a day through the intrathecal catheter. Results: Intrathecal EGCG increased the paw withdrawal latency (PWL) after repeated administration for 7 days at twice a day, but this did not happen with administering on single bolus injection of EGCG. In addition, the antinociceptive effect of intrathecal morphine was not affected by co-administration with EGCG. A continuous 7-day infusion of morphine caused a significant decrease of the PWL in the control group (M + S, morphine plus saline). In contrast, intrathecal EGCG injection over 7 days blocked the decrease of the PWL in the experiment group (M + E, morphine plus EGCG). Conclusions: Intrathecal ECGC produced a weak antinociceptive effect for acute thermal pain, but it did not change the morphine's analgesic effect. However, the development of antinociceptive tolerance to morphine was attenuated by administering intrathecal EGCG.

• Journal of Korean Neurosurgical Society
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• v.49 no.2
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• pp.83-91
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• 2011

Objective : Minocycline, a second-generation tetracycline-class antibiotic, has been well established to exert a neuroprotective effect in animal models and neurodegenerative disease through the inhibition of microglia. Here, we investigated the effects of minocycline on motor recovery and neuropathic pain in a rat model of spinal cord injury. Methods : To simulate spinal cord injury, the rats' spinal cords were hemisected at the 10th thoracic level (T10). Minocycline was injected intraperitoneally, and was administered 30 minutes prior surgery and every second postoperative day until sacrifice 28 days after surgery. Motor recovery was assessed via the Basso-Beattie-Bresnahan test Mechanical hyperalgesia was measured throughout the 28-day post -operative course via the von Frey test Microglial and astrocyte activation was assessed by immunohistochemical staining for ionized calcium binding adaptor molecule 1 (lba1) and glial fibrillary acidic protein (GFAP) at two sites: at the level of hemisection and at the 5th lumbar level (L5). Results : In rats, spinal cord hemisection reduced locomotor function and induced a mechanical hyperalgesia of the ipsilateral hind limb. The expression of lba1 and GFAP was also increased in the dorsal and ventral horns of the spinal cord at the site of hemisection and at the L5 level. Intraperitoneal injection of minocycline facilitated overall motor recovery and attenuated mechanical hyperalgesia. The expression of lba1 and GFAP in the spinal cord was also reduced in rats treated with minocycline. Conclusion : By inhibiting microglia and astrocyte activation, minocycline may facilitate motor recovery and attenuate mechanical hyperalgesia in individuals with spinal cord injuries.

• Biomolecules & Therapeutics
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• v.25 no.4
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• pp.441-451
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• 2017

Imperatorin, a major bioactive furanocoumarin with multifunctions, can be used for treating neurodegenerative diseases. In this study, we investigated the characteristics of imperatorin transport in the brain. Experiments of the present study were designed to study imperatorin transport across the blood-brain barrier both in vivo and in vitro. In vivo study was performed in rats using single intravenous injection and in situ carotid artery perfusion technique. Conditionally immortalized rat brain capillary endothelial cells were as an in vitro model of blood-brain barrier to examine the transport mechanism of imperatorin. Brain distribution volume of imperatorin was about 6 fold greater than that of sucrose, suggesting that the transport of imperatorin was through the blood-brain barrier in physiological state. Both in vivo and in vitro imperatorin transport studies demonstrated that imperatorin could be transported in a concentration-dependent manner with high affinity. Imperatorin uptake was dependent on proton gradient in an opposite direction. It was significantly reduced by pretreatment with sodium azide. However, its uptake was not inhibited by replacing extracellular sodium with potassium or N-methylglucamine. The uptake of imperatorin was inhibited by various cationic compounds, but not inhibited by TEA, choline and organic anion substances. Transfection of plasma membrane monoamine transporter, organic cation transporter 2 and organic cation/carnitine transporter 2/1 siRNA failed to alter imperatorin transport in brain capillary endothelial cells. Especially, tramadol, clonidine and pyrilamine inhibited the uptake of [$^3H$]imperatorin competitively. Therefore, imperatorin is actively transported from blood to brain across the blood-brain barrier by passive and carrier-mediated transporter.

• The Korean Journal of Food And Nutrition
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• v.31 no.4
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• pp.457-463
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• 2018

In this study, we analyzed the protective effects of the vitamin C in the streptozotocin (STZ)-induced apoptosis using the SH-SY5Y, a neuroblastoma cell line. The cells were pretreated with the vitamin C ($100{\mu}g$) for 30 min, followed by the 24-hr treatment with the 2.5-mM STZ. The cell-viability assay using the Cell Counting Kit (CCK)-8 revealed the cell-survival rate increased by 15% following the vitamin-C pretreatment compared to the STZ-only treatment. Moreover, we conducted the western-blot analysis to determine the protective effect of the vitamin C regarding the apoptosis. Compared to those in the STZ-only-treatment group, the p-ERK and Bcl-2 expressions increased in the vitamin-C-pretreatment group, whereas the p-JNK and Bax expressions decreased. The vitamin-C pretreatment increased the expression of the SOD-1, an antioxidant enzyme, by more than 30%, indicating its protective role in the STZ-induced oxidative stress. Also, we found both the intrinsic- and extrinsic-pathway mechanisms of the STZ-induced apoptosis. The results of this study $s{\mu}ggest$ vitamin C may help prevent the neurodegenerative diseases.

• IMMUNE NETWORK
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• v.6 no.3
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• pp.128-137
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• 2006

Background: Apoptosis is a physiologic phenomenon involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. The mouse myeloma cell P3-X63-Ag8.653 (v653) is an HGPRT deficient $(HGPRT^-)$ mutant strain. High dependency on de novo transcription and translation of aminopterin induced apoptosis of this cell seems to be an ideal experimental system for searching apoptosis-induced genes. Methods & Results: For searching apoptosis-related genes we carried out GE-array (dot blot), Affymetrix GeneChip analysis, Northern analysis and differential display-PCR techniques. The chip data were analyzed with three different programs. 66 genes were selected through Affymetrix GeneChip analyses. All genes selected were classified into 8 groups according to their known functions. They were Genes of 1) Cell growth/maintenance/death/enzyme, 2) Cell cycle, 3) Chaperone, 4) Cancer/disease-related genes, 5) Mitochondria, 6) Membrane protein/signal transduction, 7) Nuclear protein/nucleic acid binding/transcription binding and 8) Translation factor. Among these groups number of genes were the largest in the genes of cell growth/maintenance/death/enzyme. Expression signals of most of all groups were peaked at 3 hour of apoptosis except genes of Nuclear protein/nucleic acid binding/transcription factor which showed maximum signal at 1 hour. Conclusion: This study showed induction of wide range of proapoptotic factors which accelerate cell death at various stage of cell death. In addition apoptosis studied in this research can be classified as a type 2 which involves cytochrome c and caspase 9 especially in early stages of death. But It also has progressed to type 1 in late stage of the death process.

• Biomolecules & Therapeutics
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• v.20 no.2
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• pp.214-219
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• 2012

This research was designed to determine what components of Gardenia jasminoides play a major role in inhibiting the enzymes related antidepressant activity of this plant. In our previous research, the ethyl acetate fraction of G. jasminosides fruits inhibited the activities of both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B), and oral administration of the ethanolic extract slightly increased serotonin concentrations in the brain tissues of rats and decreased MAO-B activity. In addition, we found through in vitro screening test that the ethyl acetate fraction showed modest inhibitory activity on dopamine-${\beta}$ hydroxylase (DBH). The bioassay-guided fractionation led to the isolation of five bio-active compounds, protocatechuic acid (1), geniposide (2), 6'-O-trans-p-coumaroylgeniposide (3), 3,5-dihydroxy-1,7-bis(4-hydroxyphenyl) heptanes (4), and ursolic acid (5), from the ethyl acetate fraction of G. jasminoides fruits. The isolated compounds showed different inhibitory potentials against MAO-A, -B, and DBH. Protocatechuic acid showed potent inhibition against MAO-B ($IC_{50}$ $300{\mu}mol/L$) and DBH ($334{\mu}mol/L$), exhibiting weak MAO-A inhibition (2.41 mmol/L). Two iridoid glycosides, geniposide ($223{\mu}mol/L$) and 6'-O-trans-p-coumaroylgeniposide ($127{\mu}mol/L$), were selective MAO-B inhibitor. Especially, 6'-O-trans-p-coumaroylgeniposide exhibited more selective MAO-B inhibition than deprenyl, well-known MAO-B inhibitor for the treatment of early-stage Parkinson's disease. The inhibitory activity of 3,5-dihydroxy-1,7-bis (4-hydroxyphenyl) heptane was strong for MAO-B ($196{\mu}mol/L$), modest for MAO-A ($400{\mu}mol/L$), and weak for DBH ($941{\mu}mol/L$). Ursolic acid exhibited significant inhibition of DBH ($214{\mu}mol/L$), weak inhibition of MAO-B ($780{\mu}mol/L$), and no inhibition against MAO-A. Consequently, G. jasminoides fruits are considerable for development of biofunctional food materials for the combination treatment of depression and neurodegenerative disorders.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.175-181
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• 2018

Carbon monoxide (CO) is well-known as toxic gas and intrinsic signaling molecule such as neurotransmitter and blood vessel relaxant. Recently, it has been reported that low concentration of CO exerts therapeutic actions under various pathological conditions including liver failure, heart failure, gastric cancer, and cardiac arrest. However, little has been known about the effect of CO in neurodegenerative diseases like Parkinson's disease (PD). To test whether CO could exert a beneficial action during oxidative cell death in PD, we examined the effects of CO on 6-hydroxydopamine (6-OHDA)-induced cell death in C6 glioma cells. Treatment of CO-releasing molecule-2 (CORM-2) significantly attenuated 6-OHDA-induced apoptotic cell death in a dose-dependent manner. CORM-2 treatment decreased Bax/Bcl2 ratio and caspase-3 activity, which had been increased by 6-OHDA. CORM-2 increased phosphorylation of NF-E2-related factor 2 (Nrf2) which is a transcription factor regulating antioxidant proteins. Subsequently, CORM-2 also increased the expression of heme oxygenase-1 and superoxide dismutases (CuZnSOD and MnSOD), which were antioxidant enzymes regulated by Nrf2. These results suggest that CO released by CORM-2 treatment may have protective effects against oxidative cell death in PD through the potentiation of cellular adaptive survival responses via activation of Nrf2 and upregulation of heme oxygenase-1, leading to increasing antioxidant defense capacity.

• YAKHAK HOEJI
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• v.60 no.2
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• pp.92-99
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• 2016

Parkinson's disease (PD) is one of the representative neurodegenerative movement disorders with the selective loss of dopaminergic neurons in the substantia nigra. 6-Hydroxydopamine (6-OHDA) is widely used as an experimental model system to mimic PD and has been reported to cause neuronal cell death via oxidative and/or nitrosative stress. Therefore, daily intake of dietary or medicinal plants which fortifies cellular antioxidant capacity can exert neuroprotective effects in PD. In the present study, we have investigated the protective effect of Korean red ginseng (KRG) against 6-OHDA-induced nitrosative death in C6 glioma cells. Treatment of C6 cells with 6-OHDA decreased cell viability and increased expression of inducible nitric oxide synthase, production of nitric oxide as well as peroxynitrite, and formation of nitrotyrosine. 6-OHDA led to apoptotic cell death as determined by decreased Bcl-2/Bax, phosphorylation of JNK, activation of caspase-3, and cleavage of PARP. Conversely, pretreatment of C6 cells with KRG attenuated 6-ODHA-induced cytotoxicity, apoptosis, and nitrosative damages. To further elucidate the molecular mechanism of KRG protection against 6-OHDA-induced nitrosative cell death, we have focused on the cellular self-defense molecules against exogenous noxious stimuli. KRG treatment up-regulated heme oxygenase-1 (HO-1), a key antioxidant enzyme essential for cellular defense against oxidative and/or nitrosative stress via activation of Nrf2. Taken together, these findings suggest KRG may have preventive and/or therapeutic potentials for the management of PD.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.4
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• pp.399-406
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• 2016

Early life neuronal exposure to environmental toxicants has been suggested to be an important etiology of neurodegenerative disease development. Perfluorohexanesulfonate (PFHxS), one of the major perfluoroalkyl compounds, is widely distributed environmental contaminants. We have reported that PFHxS induces neuronal apoptosis via ERK-mediated pathway. Imperatorin is a furanocoumarin found in various edible plants and has a wide range of pharmacological effects including neuroprotection. In this study, the effects of imperatorin on PFHxS-induced neuronal apoptosis and the underlying mechanisms are examined using cerebellar granule cells (CGC). CGC were isolated from seven-day old rats and were grown in culture for seven days. Caspase-3 activity and TUNEL staining were used to determine neuronal apoptosis. PFHxS-induced apoptosis of CGC was significantly reduced by imperatorin and PD98059, an ERK pathway inhibitor. PFHxS induced a persistent increase in intracellular calcium, which was significantly blocked by imperatorin, NMDA receptor antagonist, MK801 and the L-type voltage-dependent calcium channel blockers, diltiazem and nifedipine. The activation of caspase-3 by PFHxS was also inhibited by MK801, diltiazem and nifedipine. PFHxS-increased ERK activation was inhibited by imperatorin, MK801, diltiazem and nifedipine. Taken together, imperatorin protects CGC against PFHxS-induced apoptosis via inhibition of NMDA receptor/intracellular calcium-mediated ERK pathway.

• Journal of the Korean Institute of Intelligent Systems
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• v.24 no.6
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• pp.609-614
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• 2014

Cerebellar ataxia is a steadily progressive neurodegenerative disease associated with loss of motor control, leaving patients unable to walk, talk, or perform activities of daily living. Direct motor instruction in cerebella ataxia patients has limited effectiveness, presumably because an inappropriate closed-loop cerebellar response to the inevitable observed error confounds motor learning mechanisms. Recent studies have validated the age-old technique of employing motor imagery training (mental rehearsal of a movement) to boost motor performance in athletes, much as a champion downhill skier visualizes the course prior to embarking on a run. Could the use of EEG based BCI provide advanced biofeedback to improve motor imagery and provide a "backdoor" to improving motor performance in ataxia patients? In order to determine the feasibility of using EEG-based BCI control in this population, we compare the ability to modulate mu-band power (8-12 Hz) by performing a cued motor imagery task in an ataxia patient and healthy control.