• 생명과학회지
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• 제15권3호
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• pp.505-512
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• 2005

신경흥분독성과 간질발작발현은 glutamate 수용체활성과 연관이 있다고 알려져 있다. a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), kainate 수용체에 대한 glutamate 활성을 포함하는 다양한 기전을 가진 항전간제인 Topiramate는 신경보호작용을 가진다는 증거가 제시되어 Topiramate가 간질발작 후 해마의 glutamate 수용체 발현에 미치는 효과를 관찰하였다. 흰쥐에 kainate를 복강 내 주사하여 간질중첩증을 유발시킨 후 Topiramate를 1주일 주사하였다 Apop tag in situ detection kit를 이용하여 세포손상을 관찰한 결과 kainate 유발 간질중첩증 1주일 후 해마의 CA1, CA3에서 심각한 세포사를 보였으나, Topiramte 처리 군에서는 세포사가 현저히 감소하였다. 간질중첩증 이후 NMDA 수용체 아형 1,2a, 2b 발현이 현저히 증가했으나 Topiramate 처치에 의해 NMDA수용체의 발현에는 뚜렷한 변화가 없었다. AMPA수용체에서는 GluR1이 간질중첩증 이후 현저히 상향 조정되었고 GluR2는 현저히 하향조정 되었다 Topiramate 1주일 처리 시 간질중첩증으로 인해 변화된 CluR1과 GluR2의 발현이 역전되었다. 결론적으로 Topiramate는 간질중침증에 의한 CluR1/CluR2 발현비의 증가로 유발되는 흥분성 신경세포사를 억제시킴으로써 신경보호작용이 있는 것으로 보인다.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.72-74
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• 2003

Excitatory amino acid (EAA) receptor, particularly NMDA receptor, are now known to be one of major transmitter receptors involved in synaptic excitation. Excessive release of EAA neurotransmitter, glutamate, is an important causative factor in the neurodegenerative processes and can cause neuronal damage and cell death. This excitotoxicity has been shown to be $Ca^{++}$ dependent. (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.191.1-191.1
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• 2000

• Biomolecules & Therapeutics
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• 제19권4호
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• pp.445-450
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• 2011

Preciously, we demonstrated that a novel NHE-1 inhibitor, KR-33028 attenuated cortical neuronal apoptosis induced by glutamate. In the present study, we investigated the signaling mechanism of neuroprotective effect of KR-33028 against glutamate-induced neuronal apoptosis, especially focusing on mitochondrial death pathway. Our data showed that glutamate induces a biphasic rise in mitochondrial $Ca^{2+}$ and that KR-33028 significantly prevents the second phase increase, but not the first phase increase in mitochondrial $Ca^{2+}$. Furthermore, KR-33028 restored the ${\Delta}{\Psi}_m$ dissipation and cytochrome c release into cytoplasm induced by glutamate in a concentration-dependent manner. The inhibition of mitochondrial $Ca^{2+}$ overload by ruthenium red also inhibited glutamate-induced apoptotic cell death, mitochondrial membrane potential, ${\Delta}{\Psi}_m$ dissipation and cytochrome c release. These data suggest that inhibition of mitochondrial $Ca^{2+}$ overload is likely to be attributable to anti-apoptotic effect of KR-33028. Taken together, our results suggest that anti-apoptotic effects of NHE-1 inhibitor, KR-33028 may be mediated through maintenance of mitochondrial function.

• BMB Reports
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• 제49권2호
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• pp.69-70
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• 2016

Mutations of orthodentricle homeobox 2 (OTX2) in human and mice often cause retinal dystrophy and nyctalopia, suggesting a role of OTX2 in mature retina, in addition to its functions in the development of the eye and retina. In support of this, the number of bipolar cells in Otx2^+/− post-natal mouse retina was found to be significantly lower than normal. Degeneration of the cells becomes greater as the mice age, leading to the loss of vision. Especially, the type-2 OFF-cone bipolar cells, which do not express Otx2 mRNA but carry Otx2 protein, are most sensitive to Otx2 haplodeficiency. Interestingly, this bipolar cell subpopulation imports Otx2 protein from photoreceptors to protect itself from glutamate excitotoxicity in the dark. Moreover, in the bipolar cells, the exogenous Otx2 relocates to the mitochondria to support mitochondrial ATP synthesis. This novel mitochondrial activity of exogenous Otx2 highlights the therapeutic potential of Otx2 protein transduction in retinal dystrophy.

• Archives of Pharmacal Research
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• 제29권8호
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• pp.699-706
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• 2006

The present study evaluated antioxidant and neuroprotective activities of hesperidin, a flavanone mainly isolated from citrus fruits, and its aglycone hesperetin using cell-free bioassay system and primary cultured rat cortical cells. Both hesperidin and hesperetin exhibited similar patterns of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activities. While hesperidin was inactive, hesperetin was found to be a potent antioxidant, inhibiting lipid peroxidation initiated in rat brain homogenates by $Fe^{2+}$ and L-ascorbic acid. In consistence with these findings, hesperetin protected primary cultured cortical cells against the oxidative neuronal damage induced by $H_2O_2$ or xanthine and xanthine oxidase. In addition, it was shown to attenuate the excitotoxic neuronal damage induced by excess glutamate in the cortical cultures. When the excitotoxicity was induced by the glutamate receptor subtype-selective ligands, only the N-methyl-D-aspartic acid-induced toxicity was selectively and markedly inhibited by hesperetin. Furthermore, hesperetin protected cultured cells against the $A_{{\beta}(25-35)}-induced$ neuronal damage. Hesperidin, however, exerted minimal or no protective effects on the neuronal damage tested in this study. Taken together, these results demonstrate potent antioxidant and neuroprotective effects of hesperetin, implying its potential role in protecting neurons against various types of insults associated with many neurodegenerative diseases.

• 약학회지
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• 제43권4호
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• pp.535-540
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• 1999

Glutamate (Glu) receptor-mediated excitoxicity has been implicated in many acute and chronic types of neurological disorders. Exposure of mature rat cortical neurons (15-18 days in culture) to the various concentrations of Glu resulted in a marked neuronal death, whereas immature rat cortical neurons (4∼5 days in culture) were resistant to the Glu-induced toxicity. Glu receptor subtype-specific agonists showed differential extent of toxicity in the immature neurons. The neurons treated with NMDA or kainate (KA) did not exhibit damage. However, quisqualate (QA) treatment induced a considerable cell death (36.1%) in immature enurons. The non-NMDA antagonist DNQX did not reduce this response. Interestingly, the QA-induced toxicity was potentiated by spermine in a concentration-dependent manner. Again, the spermine-enhanced damage was not altered by the polyamine antagonist ifenprodil. Taken together, unlike NMDA or KA, QA can induce neurotoxicity in immature rat cortical neurons and the QA-induced toxicity was potentiated by spermine. The lack of antagonizing effects of DNQX and ifenprodil on QA-induced toxicity and the potentiated toxicity by spermine, respectively, implies that both QA receptor and the polyamine site of NMDA receptor may not mediate the neurotoxicity observed in this study, and that a distinct mechanism(s) may be involved in excitotoxicity in immature neurons.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.699-705
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• 1997

Although it is known that neuronal cell death during development occurs by apoptosis, the mechanisms underlying excitatory amino acid-induced neuronal cell death remain poorly understood. In this study we have examined the mechanism by which L-glutamate, an excitatory amino acid neurotransmitter, induces cell death in PC12 cell lines. To characterize cell death, we employed sandwich enzyme-linked immunosorbent assay(ELISA) method for cellular DNA fragmentation, DNA agarose gel electrophoresis and chromatin staining by acridine orange and ethidium bromide after treating the PC12 cells with L-glutamate. L-Glutamate caused dose-dependent cell death with a maximum at 24 hrs after the treatment. These cellular fragmentation was blocked by pretreatment of MK-801, a noncompetitive N-methyl-D-aspartic acid(NMDA) receptor antagonist, and nerve growth factor(NGF). Analysis of DNA integrity from L-glutamate-treated cells revealed cleavage of DNA into regular sized fragments, a biochemical hallmark of apoptosis. The PC12 cells that were induced to die by L-glutamate treatment exhibited classical chromatin condensation under the light microscopy after acridine orange and ethidium bromide staining. These results suggest that apoptosis is one of the key features that are involved in L-glutamate-induced excitotoxic cell death in PC12 cells, and these cell death are mediated by NMDA receptor and depend on NGF.

• 약학회지
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• 제45권4호
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• pp.419-425
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• 2001

The neuronal cell death induced by excess glutamate (Glu) has been implicated in many acute and chronic neurodegenerative diseases including cerebral ischemia. Glu-induced elevation of intra-cellular $Ca^{2+}$ plays a critical role in the excitotoxicity, partly through the activation of a variety of $Ca^{2+}$ dependent enzymes. In the present study, we investigated the Glu-induced modulation of $Ca^{2+}$/calmodulin-dependent protein kinase IV (CaMK IV), a multifunctional enzyme abundantly present in the nuclei of neurons. The exposure of cultured rat cortical neurons to $100{\mu}$M Glu for 3 min dramatically increased CaMK IV activity up to 4.5-fold of the control-treated enzyme activity. The activation was very rapid, reaching peak at 3 min and then declined gradually. Under the same experimental conditions, time-dependent acute and delayed neuronal cell death was observed. Immunoblot analyses using specific antibodies showed that the expressions of CaMK IV and $CaMKK_{\alpha}$ were time-dependently modulated by Glu. Taken together, these results imply that the modulation of CaMK IV activity by Glu may be involved in the cascade of events resulting in neuronal cell death in cortical cultures.

• 생약학회지
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• 제39권3호
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• pp.213-217
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• 2008

Oxidative stress is considered to play an important role in a variety of neurodegenerative disorders of central nervous system. The immortalized mouse hippocampal cell line, HT22, phenotypically resembles neuronal precursor cells but lacks functional ionotropic glutamate receptors, thus excluding excitotoxicity as a cause for glutamate triggered cell death. Therefore, HT22 cells are a useful model for studying oxidative glutamate toxicity. In this study, we examined whether the methanol extracts of some native plants at Mt. Baekdu could protect HT22-immortalized hippocampal cells against glutamate-induced oxidative stress. Seventy-eight plants sources were collected at Mt. Baekdu, and extracted with methanol. These extracts had been screened the protective effects against glutamate-induced oxidative damage in HT22 cells at the 100 and 300 ${\mu}g/ml$. Of these, thirteen methanolic extracts, Acer mono (leaf), Artemisia stolonifera (aerial part), Carduus crispus (aerial part), Carex mongolica (whole plant), Clematis hexapetala (whole plant), Galeopsis bifida (aerial part), Galium verum (whole plant), Ganoderma lucidum (whole plant), Ixeris chinensis (whole plant), Malva verticillata (aerial part), Polygonum senticosum (whole plant), Rebes mandshricum (branch), and Taraxacum mongolicum (aerial part), showed significant protective effects against glutamate-induced oxidative damage in HT22 cells.