Effect of glutamate on lysosomal membrane permeabilization in primary cultured cortical neurons.
Mol Med Rep
; 13(3): 2499-505, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26821268
ABSTRACT
Glutamate is the principal neurotransmitter in the central nervous system. Glutamate-mediated excitotoxicity is the predominant cause of cerebral damage. Recent studies have shown that lysosomal membrane permeabilization (LMP) is involved in ischemiaassociated neuronal death in nonhuman primates. This study was designed to investigate the effect of glutamate on lysosomal stability in primary cultured cortical neurons. Glutamate treatment for 30 min induced the permeabilization of lysosomal membranes as assessed by acridine orange redistribution and immunofluorescence of cathepsin B in the cytoplasm. Inhibition of glutamate excitotoxicity by the NMDA receptor antagonist MK801 and the calcium chelator ethylene glycolbis (2aminoethylether)N, N, N', N'tetraacetic acid, rescued lysosomes from permeabilization. The role of calpain and reactive oxygen species (ROS) in inducing LMP was also investigated. Ca2+ overload following glutamate treatment induced the activation of calpain and the production of ROS, which are two major contributors to neuronal death. It has been reported that lysosomalassociated membrane protein 2 (LAMP2) and heat shock protein (HSP)70 are two calpain substrates that promote LMP in cancer cells; however, it was found that calpains were activated by glutamate, but only LAMP2 was subsequently degraded. Furthermore, LMP was not alleviated by treatment with the calpain inhibitors calpeptin and SJA6017, which blocked the cleavage of the calpain substrate αfodrin. It was demonstrated that LMP was significantly alleviated by treatment with the antioxidant NAcetylLcysteine, indicating that LMP involvement in early glutamate excitotoxicity may be mediated partly by ROS rather than calpain activation. Overall, these data shed light on the role of ROS-mediated LMP in early glutamate excitotoxicity.
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Base de dados:
MEDLINE
Assunto principal:
Ácido Glutâmico
/
Lisossomos
/
Neurônios
Limite:
Animals
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2016
Tipo de documento:
Article