• The Korean Journal of Pain
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• v.28 no.2
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• pp.96-104
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• 2015

Background: The present experiment was conducted to identify the cooperative effect of serine histogranin (SHG) and noradrenaline in alleviating peripheral neuropathic pain. Methods: Chronic constriction injury of the right sciatic nerve was used to induce chronic neuropathic pain. For drug delivery, a PE10 tube was inserted into the subarachnoid space. Acetone drops and a $44^{\circ}C$ water bath were used to evaluate the cold and heat allodynia, respectively. Placing and grasping reflexes were used to assess the locomotor system. Results: SHG at 0.5 and $1{\mu}g$significantly (P < 0.05) decreased the thermal allodynia. The cold allodynia was also significantly reduced by intrathecal injections of 0.5 (P < 0.05) and $1{\mu}g$(P < 0.001) of SHG. $1{\mu}g$of noradrenaline, but not $0.5{\mu}g$, significantly alleviated the cold (P < 0.01) and thermal (P < 0.05) allodynia. The ameliorating effect of noradrenaline or SHG disappeared when the two compounds were administrated in equal concentrations. A significant difference (P < 0.01 in the acetone and P < 0.05 in the heat) was observed in the groups under equal doses of the two compounds, with a lower effectiveness of the combination therapy. Conclusions: Our findings suggest that the simultaneous administrations of noradrenaline and SHG do not result in synergistic analgesia, and combination therapy may not be a good approach to the treatment of chronic neuropathic pain syndrome.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.673-679
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• 1997

It has been generally accepted that glutamate mediates the ischemic brain damage, excitotoxicity, and induces release of neurotransmitters, including norepinephrine(NE), in ischemic milieu. In the present study, the role of nitric oxide(NO) in the ischemia-induced $[^3H]norepinephrine([^3H]NE)$ release from cortex slices of the rat was examined. Ischemia, deprivation of oxygen and glucose from $Mg^{2+}-free$ artificial cerebrospinal fluid, induced significant release of $[^3H]NE$ from cortex slices. This ischemia-induced $[^3H]NE$ release was significantly attenuated by glutamatergic neurotransmission modifiers. $N^G-nitro-L-arginine$ methyl ester(L-NAME), $N^G-monomethyl-L-arginine$ (L-NMMA) or 7-nitroindazole, nitric oxide synthase inhibitors attenuated the ischemia-evoked $[^3H]NE$ release. Hemoglobin, a NO chelator, and 5, 5- dimethyl-L-pyrroline-N-oxide(DMPO), an electron spin trap, inhibited $[^3H]NE$ release dose-dependently. Ischemia-evoked $[^3H]NE$ release was inhibited by methylene blue, a soluble guanylate cyclase inhibitor, and potentiated by 8-bromo-cGMP, a cell permeable cGMP analog, zaprinast, a cGMP phosphodiesterase inhibitor, and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide generator. These results suggest that the ischemia-evoked $[^3H]NE$ release is mediated by NMDA receptors, and activation of NO system is involved.

• Archives of Pharmacal Research
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• v.20 no.1
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• pp.39-45
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• 1997

Changes in glutamatergic nervous activities following intracerebroventricular (icv) administration of ethylcholine aziridinium (AF64A) were studied in rats. The levels of total glutamate, those of glutamate in cerebrospinal fluid (CSF) and in extracellular fluid (ECF) of striatum, the activities of glutamine synthetase (GS), glutaminase and glutamate dehydrogenase (GDH) and the specific binding sites of $[^3H]$MK801 in striatum, hippocampus and frontal cortex were assessed a week after the infusion of AF64A (3 nmol) into lateral ventricle. The levels of total glutamate were significantly decreased in striatum, hippocampus and frontal cortex after AF64A treatment. Although the levels of glutamate in CSF weren't changed after AF64A treatment, the levels of glutamate in ECF of striatum were significantly decreased (62.6%). GS activities in striatum were significantly decreased. But, glutaminase activities in striatum were significantly increased. However, the activities of GS and glutaminase in frontal cortex and hippocampus weren't changed. Although GDH activities in frontal cortex were significantly decreased, those in striatum and hippocampus weren't altered. The striatal densities of $[^3H]$MK 801 binding sites were increased without changes in its affinity. Also, the specific binding sites of $[^3H]$MK801 were increased in frontal cortex but not in hippocampus. These results indicate that the glutamatergic nervous activities were altered with the infusion of AF64A into lateral ventricle. Furthermore, it suggest that the decreased levels of glutamate after AF64A treatment may affect the change in the other parameters of glutamatergic neuronal activities.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2008.04a
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• pp.33-45
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• 2008

Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy. The conditioning-induced potentiation has been shown to be maintained, at least in part, by enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a cellular mechanism for fear extinction. However, a direct link between depotentiation and extinction has not yet been tested. To address this, we applied both ex vivo and in vivo approaches to rats in which fear memory had been consolidated. We found a novel form of ex vivo depotentiation; the depotentiation reversed conditioning-induced potentiation at thalamic input synapses onto the LA (T-LA synapses) ex vivo, and it could be induced only when both NMDA and metabotropic glutamate receptors were co-activated. Extinction returned the enhanced T-LA synaptic efficacy observed in conditioned rats to baseline and occluded the depotentiation. Consistently, extinction reversed conditioning-induced enhancement of surface expression of AMPAR subunits in LA synaptosomal preparations. A GluR2-derived peptide that blocks regulated AMPAR endocytosis inhibited depotentiation, and microinjection of a cell-permeable form of the peptide into the LA attenuated extinction. Our results are consistent with the use of depotentiation to weaken potentiated synaptic inputs onto the LA during extinction, and they provide strong evidence that AMPAR removal at excitatory synapses in the LA underlies extinction. The results described here are in line with previous findings. Neural activity in the LA has been shown to decrease after extinction in the rat and human. The NMDAR dependency of the depotentiation fits nicely with a large body of evidence that fear extinction depends upon amygdala NMDARs. Similarly, blockade of metabotropic glutamate recepotrs in the LA has recently been shown to attenuate fear extinction.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.109-114
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• 2018

Liquiritigenin (LQ) is a flavonoid that can be isolated from Glycyrrhiza radix. It is frequently used as a tranditional oriental medicine herbal treatment for swelling and injury and for detoxification. However, the effects of LQ on cognitive function have not been fully explored. In this study, we evaluated the memory-enhancing effects of LQ and the underlying mechanisms with a focus on the N-methyl-D-aspartic acid receptor (NMDAR) in mice. Learning and memory ability were evaluated with the Y-maze and passive avoidance tests following administration of LQ. In addition, the expression of NMDAR subunits 1, 2A, and 2B; postsynaptic density-95 (PSD-95); phosphorylation of $Ca^{2+}$/calmodulin-dependent protein kinase II (CaMKII); phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2); and phosphorylation of cAMP response element binding (CREB) proteins were examined by Western blot. In vivo, we found that treatment with LQ significantly improved memory performance in both behavioral tests. In vitro, LQ significantly increased NMDARs in the hippocampus. Furthermore, LQ significantly increased PSD-95 expression as well as CaMKII, ERK, and CREB phosphorylation in the hippocampus. Taken together, our results suggest that LQ has cognition enhancing activities and that these effects are mediated, in part, by activation of the NMDAR and CREB signaling pathways.

• Biomolecules & Therapeutics
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• v.15 no.1
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• pp.16-26
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• 2007

Tissue plasminogen activator (tPA) is a serine protease catalyzing the proteolytic conversion of plasminogen into plasmin, which is involved in thrombolysis. During last two decades, the role of tPA in brain physiology and pathology has been extensively investigated. tPA is expressed in brain regions such as cortex, hippocampus, amygdala and cerebellum, and major neural cell types such as neuron, astrocyte, microglia and endothelial cells express tPA in basal status. After strong neural stimulation such as seizure, tPA behaves as an immediate early gene increasing the expression level within an hour. Neural activity and/or postsynaptic stimulation increased the release of tPA from axonal terminal and presumably from dendritic compartment. Neuronal tPA regulates plastic changes in neuronal function and structure mediating key neurologic processes such as visual cortex plasticity, seizure spreading, cerebellar motor learning, long term potentiation and addictive or withdrawal behavior after morphine discontinuance. In addition to these physiological roles, tPA mediates excitotoxicity leading to the neurodegeneration in several pathological conditions including ischemic stroke. Increasing amount of evidence also suggest the role of tPA in neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis even though beneficial effects was also reported in case of Alzheimer's disease based on the observation of tPA-induced degradation of $A{\beta}$ aggregates. Target proteins of tPA action include extracellular matrix protein laminin, proteoglycans and NMDA receptor. In addition, several receptors (or binding partners) for tPA has been reported such as low-density lipoprotein receptor-related protein (LRP) and annexin II, even though intracellular signaling mechanism underlying tPA action is not clear yet. Interestingly, the action of tPA comprises both proteolytic and non-proteolytic mechanism. In case of microglial activation, tPA showed non-proteolytic cytokine-like function. The search for exact target proteins and receptor molecules for tPA along with the identification of the mechanism regulating tPA expression and release in the nervous system will enable us to better understand several key neurological processes like teaming and memory as well as to obtain therapeutic tools against neurodegenerative diseases.

• The Journal of Internal Korean Medicine
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• v.25 no.3
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• pp.461-472
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• 2004

Objectives : For the screening of neuroprotective effects of medicinal herbs, the complex system of animal models suffer some disadvantages in controlling critical parameters such as blood pressure and body temperature. Additionally, application of drugs to the appropriate brain area sometimes is difficult, due to poor permeability though the blood brain barrier, and so potential protective effects might be masked. Methods : Organotypic hippocampal slice culture (OHSC) method has the advantages of being relatively easy to prepare and of maintaining the general structure, including tissue integrity and the connections between cells. Drugs can easily be applied and neuronal damage can easily be quantified by using tissues and culture media. This study demonstrates neuroprotective effects of Puerariae radix (葛根, PR), Salviae miltiorrhizae radix (丹蔘, SR), Rhei rhizoma (大黃, RR), and Bupleuri radix (柴胡, BR). These were screenedand compared to MK-801, antagonist of NMDA receptors, by using OHSC of 1 week-old Sprague-Dawley rats. Oxygen/glucose deprivation (OGD) were conducted in an anaerobic chamber $(85%\;N_2,\;10%\;CO_2\;and\;5%\;H_2)$ in a deoxygenated glucose-free medium for 60 minutes. Water extracts of each herbs were treated to culture media with $5\;{\mu}g/ml$ for 48 hours. Results : Neuronal cell death in the cultures was monitored by densitometric measurements of the cellular uptake of propidium iodide (PI). PI fluorescence images were obtained at 48 hours after the OGD and medicinal herb treatment. Also TUNEL-positive cells in the CAI and DG regions and LDH concentrations in culture media were measured at 48 hours after the OGD. According to measured data, MK-801, PR, SR and BR demonstrated significant neuroprotective effect against excessive neuronal cell death and apoptosis induced by the OGD insult. Especially, PR revealed similar neuroprotective effect to MK-801 and RR demonstrated weak neuroprotective effect. Conclusions : These results suggest that OHSC can be a suitable method for screening of neuroprotective effects of medicinal herbs. (This work was supported by the research program of Dongguk University and Grant 01-PJ9-PG1-01CO03-0003 from Ministry of Health & Welfare.)