• Toxicological Research
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• 제22권3호
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• pp.275-282
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• 2006

In previous our studies, we have reported that eugenol derived from Eugenia caryophyllata(Myrtaceace) exhibits acute N-methyl-D-aspartate(NMDA)- and oxygen/glucose deprivation-induced neurotoxicity in primary cortical cultures and protects hippocampal neurons from global ischemia. In this study, we investigated whether the extracts and fractions of E. caryophyllata or eugenol shows the neuroprotective effects against delayed neuronal injury evoked by NMDA or ${\alpha}$-amino-3-hydroxy-5-methylisoxazole propionate(AMPA), and oxidative damage induced by arachidonic acid-, hydrogen peroxide-, $FeCl_2$/ascorbic acid-, and buthionine sulfoximine(BSO) in primary cortical cultures. We examined the neurotoxicity of eugenol itself in cultures and inhibitory effect of eugenol on NMDA- or kainate(KA)-induced convulsion in BALB/c mice. Each water, methanol extract and methanol fraction of E. caryophyllata was significantly attenuated NMDA-induced delayed neurotoxicity, respectively. Eugenol exhibited a significant inhibitory action against the convulsion evoked by NMDA and KA, and reduced delayed or brief neurotoxicity induced by NMDA, AMPA, and various oxidative injuries. These results suggest that eugenol derived from E. caryophyllata may contribute the neuroprotection against delayed-type excitotoxicity and excitotoxins-mediated convulsion through the amelioration of oxidative stress.

• Asian Pacific Journal of Cancer Prevention
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• 제17권2호
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• pp.463-466
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• 2016

Glioblastoma (GBM) is the most common and aggressive type of primary brain neoplasm. The current standard therapy for GBM consists of maximal surgical resection within safe limits, followed by radiation therapy (RT) and chemotherapy with temozolomide. Despite advances in treatment, the prognosis of GBM remains poor. Epileptic seizure is one of the most common symptoms in patients with GBM. Valproic acid (VPA), a histone deacetylase inhibitor, is often used as an anti-epileptic drug in patients with brain neoplasms due to its effectiveness and low toxicity profile. Several in vivo and in vitro studies have indicated that VPA has radiosensitizing effects for gliomas and radioprotective influence on normal brain tissue or hippocampal neurons. The results of several retrospective studies have also indicated potential benefit to improve survival of patients with GBM. Moreover, the promising treatment results of a phase 2 trial of concurrent radiation therapy, temozolomide, and VPA for patients with GBM have been recently reported. The use of VPA in patients with GBM has thus recently receiving more attention. In this article, we review the role of VPA in radiation therapy for GBM, focusing on the clinical evidence.

• The Korean Journal of Physiology and Pharmacology
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• 제20권2호
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• pp.185-192
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• 2016

Ampicillin, a ${\beta}$-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G significantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus.

• The Korean Journal of Physiology and Pharmacology
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• 제17권1호
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• pp.51-56
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• 2013

Many intracellular proteins and signaling cascades contribute to the sensitivity of N-methyl-D-aspartate receptors (NMDARs). One such putative contributor is the serine/threonine kinase, protein kinase C (PKC). Activation of PKC by phorbol 12-myristate 13-acetate (PMA) causes activation of extracellular signal-regulated kinase (ERK) and promotes the formation of new spines in cultured hippocampal neurons. The purpose of this study was to examine which PKC isoforms are responsible for the PMA-induced augmentation of long-term potentiation (LTP) in the CA1 stratum radiatum of the hippocampus in vitro and verify that this facilitation requires NMDAR activation. We found that PMA enhanced the induction of LTP by a single episode of theta-burst stimulation in a concentration-dependent manner without affecting to magnitude of baseline field excitatory postsynaptic potentials. Facilitation of LTP by PMA (200 nM) was blocked by the nonspecific PKC inhibitor, Ro 31-8220 ($10{\mu}M$); the selective $PKC{\delta}$ inhibitor, rottlerin ($1{\mu}M$); and the $PKC{\varepsilon}$ inhibitor, TAT-${\varepsilon}V1$-2 peptide (500 nM). Moreover, the NMDAR blocker DL-APV ($50{\mu}M$) prevented enhancement of LTP by PMA. Our results suggest that PMA contributes to synaptic plasticity in the nervous system via activation of $PKC{\delta}$ and/or $PKC{\varepsilon}$, and confirm that NMDAR activity is required for this effect.

• Journal of Acupuncture Research
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• 제25권1호
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• pp.1-14
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• 2008

Objectives : Delayed neuronal death(DND) of pyramidal neuronsin the CA1 regions of the hippocampus has been extensively studied following global brain ischemia, whereas little is known about DND in this highly vulnerable brain region after focal brain ischemia. The aim of the present study was to investigate the effect of Gastrodiae Elata(GA) pharmacopuncture on hippocampal neuronal apoptosis in rats with focal brain ischemic injury. Materials and methods : The neuroprotective effects of water extracts of GA were investigated in middle cerebral artery occlusion(MCAo) of Sprague-Dawley(SD) rats. Seventy-five healthy SD ratswere randomly divided into five groups following MCAo : control group with focal ischemia, saline injection group, pharmacopuncture group GA-1($0.0007mg/m{\ell}/g$), pharmacopuncture group GA-2($0.00035mg/m{\ell}/g$), pharmacopuncture group GA-3($0.00014mg/m{\ell}/g$). Results : The intensity of mGluR5 increased in the GA-1 group. The intensity of Bax and the Bax/Bcl-2 ratio decreased in the GA-1 group. The intensity of Bcl-2 increased in all the GA groups. The density of neurons stained by Cresyl violet and ChAT increased in the GA-1 group. Conclusions : Our study suggests that GA pharmacopuncture at $GB_{20}$ showed anti-apoptotic and neuroprotective effects on cholinergic neuronsin focal cerebral ischemia caused by stroke in SD rats.

• 대한본초학회지
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• 제21권4호
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• pp.189-195
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• 2006

Objectives : It has been reported previously that the roots of Scutellaria baicalensis (known as Huang-Gum in Korean, henceforth referred to as S. baicalensis) could prevent neuronal cell death after global cerebral ischemia. In Genuine Korean medicine, S. baicalensis is known to relieve fever in upper body, and it was thus thought to be able to alleviate deteriorations in brain function. Methods : The protective effects of S. baicalensis against post-stroke memory retardation using 4-vessel occlusion model were examined in the present study. Results : S. baicalensis was shown to significantly alleviate the deficits in learning and memory by increasing the fraction of time spent in the quadrant in which the platform was initially placed ($34.9\;{\pm}\;3.2%$, p < 0.05) compared to that of the ischemia group ($28.0\;{\pm}\;2.5%$). The cytoprotective effect of S. baicalensis on CA1 hippocampal neurons was evaluated by measuring the neuronal cell density. Neuronal cell density in S. baicalensis extracts-treated ischemia group ($138.0\;{\pm}\;13.6\;cells/mm^2$) was significantly increased compared to saline-treated ischemia group ($22.1 \;{\pm}\;9.3\;cells/mm^2$, p < 0.05). In the study of OX-42 immunohistochemistry, S. baicalensis could decrease the micrgial activation in hippocampus after brain ischemia. Conclusion : These results may provide experimental support for the use of S. baicalensis in treating post-stroke memory impairment.

• 대한한방내과학회지
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• 제29권3호
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• pp.608-620
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• 2008

Objectives : This study investigated the protective effects of the water extracts of Chongmyung-tang, Polygalae Radix, and Acori Graminei Rhizoma in an in vivo Alzheimer's disease (AD) mouse model. Methods : Memory impairment was induced by an intraventricular injection of $A{\beta}25-35$ peptides and subsequently Chongmyung-tang, Polygalae Radix, or Acori Graminei Rhizoma extract were administered orally for 14days. Results : In the water maze task, Chongmyung-tang, Polygalae Radix, and Acori Graminei Rhizoma extracts improved learning ability during the acquisition period and significantly increased memory scores during the retention period versus $A{\beta}-injected$ controls. Furthermore, the toxicity of $A{\beta}25-35$ on hippocampus was assessed immunohistochemically (Tau, MAP2, TUNEL, Bax) and by in vitro study. Chongmyung-tang, Polygalae Radix, and Acori Graminei Rhizoma demonstrated significant neuroprotective effects against oxidative damage and apoptotic cell death of hippocampal neurons damaged by $A{\beta}25-35$. Conclusions : These results suggested that Chongmyung-tang, Polygalae Radix and Acori Graminei Rhizoma extract improve memory impairment and reduce Alzheimer's dementia via anti-apoptotic effects and by modulating the expressions of Tau and MAP2 protein in the hippocampus.

• BMB Reports
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• 제50권3호
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• pp.126-131
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• 2017

P48 Ebp1 is expressed in rapidly proliferating cells such as cancer cells and accelerates cell growth and survival. However, its expression pattern and role in central nervous system development have not been studied. Here, we demonstrated the spatiotemporal expression pattern of p48 Ebp1 during embryonic development and the postnatal period. During embryonic development, p48 Ebp1 was highly expressed in the brain. Expression gradually decreased after birth but was still more abundant than p42 expression after birth. Strikingly, we found that p48 Ebp1 was expressed in a cell type specific manner in neurons but not astrocytes. Moreover, p48 Ebp1 physically interacted with beta tubulin but not alpha tubulin. This fits with its accumulation in distal microtubule growth cone regions. Furthermore, in injured hippocampal slices, p48 Ebp1 introduction promoted axon regeneration. Thus, we speculate that p48 Ebp1 might contribute to microtubule dynamics acting as an MAP and promotes CNS axon regeneration.

• 동의생리병리학회지
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• 제16권3호
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• pp.594-601
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• 2002

The current study was carried out to evaluate neuroprotective effects of Citri Pericarpium after transient global ischemia in gerbils. Male Mongolian gerbils weighing 60-80g were anesthetized with 2% isoflurane mixed with 30% oxygen and 70 % nitrogen. Bilateral common carotid arteries were occluded for 5 minute with microaneurysm dips. On 3 or 7 days after ischemic surgery, the gerbils were sacrificed. The brain were removed, embedded in paraffin and sectioned at 8㎛-thickness. Gerbils that received ischemic insult for 5 min showed extensive neuronal damage in the hippocampal CA1 region, and the number of viable neuronal cell was 51.0±2.5/mm, 32.2% of normal group at 7 days after ischemic surgery. In animals that underwent the extract of Citri Pericarpium treatment, the number of viable neuronal cell were significantly better preserved at 110.58±3.58/mm, 72.0% of normal group than those of ischemic group (P<0.01). In the immunohistochemistry of Bax and Bcl-2, the Citri Pericarpium treated group down-regulated the expression of Bax protein at 72hr after transient global ischemia. In contrast, Bcl-2 protein level was not changed. The appearance in TUNEL assay is similar to the pattern of Bax protein. The water extract of Citri Pericarpium significantly reduced the number of TUNEL-positive CA1 pyramidal neurons at 72hr. The results suggest that Citri Pericarpium has potential neuroprotective effects in the transient global ischemia and the increase in the ratio of Bcl-2 to Bax may contribute to the anti-apoptotic effect of Citri Pericarpium.

• Molecules and Cells
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• 제38권5호
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• pp.402-408
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• 2015

Protein O-GlcNAcylation, dictated by cellular UDP-N-acetylglucosamine (UDP-GlcNAc) levels, plays a crucial role in posttranslational modifications. The enzyme GlcNAc kinase (NAGK, E.C. 2.7.1.59) catalyzes the formation of GlcNAc-6-phosphate, which is a major substrate for the biosynthesis of UDP-GlcNAc. Recent studies have revealed the expression of NAGK in different types of cells especially in neuronal dendrites. Here, by immunocytochemistry (ICC) and immunonucleochemistry (INC) of cultured rat hippocampal neurons, HEK293T and GT1-7 cells, we have showed that NAGK immuno-reactive punctae being present in the nucleoplasm colocalized with small nuclear ribonucleoprotein-associated protein N (snRNPN) and p54NRB, which are speckle and paraspeckle markers, respectively. Furthermore, NAGK IR cluster was also found to be colocalized with GTF2H5 (general transcription factor IIH, polypeptide 5) immuno reactive punctae. In addition, relative localization to the ring of nuclear lamin matrix and to GlcNAc, which is highly enriched in nuclear pore complexes, showed that NAGK surrounds the nucleus at the cytoplasmic face of the nuclear outer membrane. By in situ proximity ligation assay (PLA) we confirmed the colocalization of NAGK with snRNPN in the nucleus and in dendrites, while we also verified the interactions of NAGK with p54NRB, and with GTF2H5 in the nucleus. These associations between NAGK with speckle, paraspeckle and general transcription factor suggest its regulatory roles in gene expression.