Mitochondrial apoptotic cell death and moderate superoxide generation upon selective activation of non-desensitizing AMPA receptors in hippocampal cultures

• Type: Article in International Scientific Journal
• Date: 2003

Authors

Rego, AC (Author) Other; Monteiro, NM (Author) Other; Silva, AP (Author) Other; Gil, J (Author) Other; Malva, JO (Author) Other; Oliveira, CR (Author) Other

Journal

Title: Journal of Neurochemistry

Vol. 86

Pages: 792-804

ISSN: 0022-3042

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 22 Citations

Scopus - 26 Citations

Other information

Authenticus ID: P-000-FR2

DOI: 10.1046/j.1471-4159.2003.01898.x

Abstract (EN): In the present work we investigated the effect of selective stimulation of non-desensitizing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the intracellular processes leading to hippocampal neuronal death and production of reactive oxygen species (ROS). Activation of AMPA receptors in the presence of cyclothiazide (CYZ), a blocker of AMPA receptor desensitization, resulted in the death of approximately 25% of neurones, which was prevented by 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)quinoxaline (NBQX), an AMPA-preferring receptor antagonist. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) protected the neurones from necrotic death induced by AMPA or NMDA receptor activation. Neurodegeneration caused by selective activation of non-desensitizing AMPA receptors, in the presence of AMPA, CYZ and MK-801, significantly decreased the number of Co2+ -positive neurones, used as a cytochemical marker of Ca2+ -permeable AMPA receptors, but maintained intracellular ATP/ADP. The AMPA-mediated apoptotic cell death involved mitochondrial cytochrome c release and the activation of caspases-1 and -3, which was prevented by NBQX. Interestingly, although selective activation of AMPA receptors was not associated with production of intracellular peroxides, a moderate increase in superoxide production was observed upon exposure to antimycin A (AA). Furthermore, increased activity of Mn- superoxide dismutase (SOD) was observed on selective activation of non-desensitizing AMPA receptors. Taken together, these data make important contributions to the elucidation of the downstream pathways activated in AMPA receptor-mediated excitotoxicity in cultured rat hippocampal neurones.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13