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1.
J Mol Med (Berl) ; 97(3): 281-289, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30675649

RESUMO

The accumulation of glutamate (Glu) in the synaptic cleft during cerebral ischemia triggers the death of neurons, causing mental or physical handicap. However, the mechanisms of the alteration in Glu homeostasis and the imbalance between the release and clearance of Glu in ischemia are not yet completely understood. Additionally, the role of Glu transporters in regulating Glu concentration in the synaptic cleft is controversial. This review aims to provide readers with an in-depth understanding of Glu transporters in the early or later stages of ischemic events, or in mild or severe cerebral ischemia via alteration of Glu transporter expression, reversal of Glu transporters function, and trafficking between membrane and cytoplasm, to further clarify whether the Glu transporters are neuroprotective or neurodegenerative during cerebral ischemia. We provide the insights for deeper understanding of the mechanism of Glu transporters regulation after different periods and severities of cerebral ischemia.

2.
Mol Med Rep ; 19(3): 1521-1528, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592287

RESUMO

Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders, including stroke, trauma and neurodegenerative diseases. Astrocytes are the main cells for the removal of glutamate in the synaptic cleft and may affect the tolerance of neurons to the glutamate excitotoxicity. Therefore, the present study aimed to investigate the tolerance of rat cortical neurons to glutamate excitotoxicity in the presence and absence of astrocytes. Rat cortical neurons in the presence or absence of astrocytes were exposed to different concentrations of glutamate (10­2,000 µM) and 10 µM glycine for different incubation periods. After 24 h, the Cell Counting kit­8 (CCK­8) assay was used to measure the cytotoxicity to neurons in the presence or absence of astrocytes. According to the results, in the absence of astrocytes, glutamate induced a concentration­dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic half­maximal inhibitory concentration (IC50) at 15, 30 and 60 min was 364.5, 258.5 and 138.3 µM, respectively. Furthermore, in the presence of astrocytes, glutamate induced a concentration­dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic IC50 at 15, 30 and 60 min was 1,935, 932.8 and 789.3 µM, respectively. However, astrocytic toxicity was not observed when the rat cortical astrocytes alone were exposed to different concentrations of glutamate (500, 1,000 and 2,000 µM) for 6, 12 and 24 h. In conclusion, the glutamate­induced neurotoxic IC50 values at 15, 30 and 60 min were respectively higher in the presence of astrocytes as compared with those in the absence of astrocytes, suggesting that astrocytes can protect against rat cortical neuronal acute damage induced by glutamate.


Assuntos
Astrócitos/metabolismo , Córtex Cerebral/efeitos dos fármacos , Ácido Glutâmico/administração & dosagem , Neurônios/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Tolerância a Medicamentos/genética , Ácido Glutâmico/toxicidade , Glicina/administração & dosagem , Glicina/efeitos adversos , Neurônios/patologia , Ratos
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 31(3): 238-43, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26387186

RESUMO

OBJECTIVE: The present study was undertaken to design antisense oligodeoxynucleotides (AS-ODNs) of glial glutamate transporter-la (GLT-1a) and to evaluate the effectiveness of the designed AS-ODNs on the expression of GLT-1a. METHODS: Five sequences of GLT-1a AS-ODNs were designed according to the C terminus specific sequences of GLT-1a mRNA using antisense design software of IDT Com- pany. Western blot analysis was used to evaluate the inhibition effects of the five GLT-1a AS-ODNs on the expression of GLT-la. RESULTS: The sequence of GLT-1a AS-ODNs with sequence of 5'-GGTTCTTCCTCAACACTGCA-3' could specifically inhibit the expression of GLT-1a in the hippocampal CA1 subfield of rats, while it had no effect on the expression of GLT-1b. This sequence showed similar inhibition on the expression of GLT-la in sham and ceftriaxone (Cef)-treated rats. It could also significantly inhibit the cerebral ischemic preconditioning (CIP)-induced up-regulation in the expression of GLT-1a. The magnitude of the inhibition in sham, Cef- or CIP-treated rats was similar by more than 60%. CONCLUSION: From the designed five sequences of GLT-1a AS-ODNs, we obtained an effective sequence which can specifically inhibit the expression of GLT-1a.


Assuntos
Região CA1 Hipocampal/metabolismo , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Oligonucleotídeos Antissenso/genética , Animais , Transportador 2 de Aminoácido Excitatório/metabolismo , Precondicionamento Isquêmico , RNA Mensageiro , Ratos , Regulação para Cima
4.
Glia ; 60(1): 112-24, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21971915

RESUMO

This study was undertaken to determine the role of glutamate transporter-1a (GLT-1a), one of the splice variants of glutamate transporter-1, in the induction of brain ischemic tolerance by cerebral ischemic preconditioning (CIP). We used a rat global cerebral ischemic model and assessed changes by neuropathological evaluation, Western blot analysis, immunohistochemistry, real-time PCR, in vivo brain microdialysis, and high performance liquid chromatography. We found that CIP induced a significant upregulation of GLT-1a expression in the CA1 hippocampus in a time course corresponding to that of neuroprotection of CIP against brain ischemia. Severe brain ischemia for 8 min induced delayed downregulation of GLT-1a, an obvious increase in glutamate concentration and delayed neuronal death of the pyramidal neurons in the CA1 hippocampus. When the animals were pretreated with CIP before the severe ischemia, the above changes normally induced by the severe ischemia were effectively prevented. Importantly, such a preventive effect of CIP on these changes was significantly inhibited by intracerebroventricular administration of GLT-1a antisense oligodeoxynucleotides, which have been proven to specifically inhibit the expression of GLT-1a protein and mRNA, and had no effect on the expression of GLT-1b. In addition, the concentration of aspartate was also elevated after severe brain ischemic insult. However, CIP had no effect on the elevated aspartate concentrations. These results indicate that GLT-1a participated in the brain ischemic tolerance induced by CIP in rats.


Assuntos
Isquemia Encefálica/fisiopatologia , Região CA1 Hipocampal/irrigação sanguínea , Região CA1 Hipocampal/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Precondicionamento Isquêmico/métodos , Aminoácidos/metabolismo , Análise de Variância , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Transportador 2 de Aminoácido Excitatório/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Masculino , Microdiálise , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Fatores de Tempo
5.
Neurochem Int ; 59(7): 1019-28, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21925558

RESUMO

It is well known that neurons in the CA3 and dentate gyrus (DG) subfields of the hippocampus are resistant to short period of ischemia which is usually lethal to pyramidal neurons in hippocampal CA1 subfield. The present study was undertaken to clarify whether the inherent higher resistance of neurons in CA3 and DG to ischemia is associated with glial glutamate transporter-1 (GLT-1) in rats. Western blot analysis and immunohistochemistry assay showed that the basal expressions of GLT-1 in both CA3 and DG were much higher than that in CA1 subfield. Mild global brain ischemia for 8 min induced delayed death of almost all CA1 pyramidal neurons and marked GLT-1 down-regulation in the CA1 subfield, but it was not lethal to the neurons in either CA3 or DG and induced GLT-1 up-regulation and astrocyte activation showed normal soma and aplenty slender processes in the both areas. When the global brain ischemia was prolonged to 25 min, neuronal death was clearly observed in CA3 and DG accompanied with down-regulation of GLT-1 expression and abnormal astrocytes represented with hypertrophic somas, but shortened processes. After down-regulating of GLT-1 expression and function by its antisense oligodeoxynucleotides or inhibiting GLT-1 function by dihydrokainate, an inhibitor of GLT-1, the mild global brain ischemia for 8 min, which usually was not lethal to CA3 and DG neurons, induced the neuronal death in CA3 and DG subfields. Taken together, the higher expression of GLT-1 in the CA3 and DG contributes to their inherent resistance to ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Giro Denteado/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Hipocampo/metabolismo , Animais , Sequência de Bases , Western Blotting , Primers do DNA , Imuno-Histoquímica , Masculino , Ratos , Ratos Wistar
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