A Bcl-2 antisense oligonucleotide increases α-amino-3-hydroxy-5- methylisoxazole-4propionic acid (AMPA) toxicity in cortical cultures

Melissa J. White, Jun Chen, R. Li Zhu, Stacy Irvin, Amy Sinor, Michael J. DiCaprio, Kunlin Jin, David A. Greenberg

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated neurotoxicity and the induction of death-regulatory genes have been implicated in the pathophysiology of delayed ischemic neuronal injury. To assess the role of the antiapoptotic gene Bcl-2 in the modulation of AMPA toxicity, we exposed neuron-enriched cultures from rat cerebral cortex to AMPA, in the absence or presence of an antisense oligodeoxynucleotide (ODN) directed against Bcl-2. AMPA produced concentration-dependent toxicity detected by a decrease in fluorescence of the redox indicator Alamar blue and by an increase in lactic acid dehydrogenase release. This effect was accompanied by the induction of Bcl-2 protein expression, with maximal induction at 100 μM AMPA. A phosphorothioate antisense ODN against Bcl-2 reduced the AMPA-stimulated induction of Bcl-2 protein levels, detected by western blotting, by about 70%. In the presence of the antisense ODN, but not sense or scrambled ODNs, the toxicity of 100 μM AMPA was increased by about 60%. These findings suggest that induction of Bcl-2 expression by AMPA may have a protective role to limit AMPA receptor-mediated neuronal damage and that modifying Bcl-2 expression could have therapeutic potential in ischemia.

Original languageEnglish
Pages (from-to)580-587
Number of pages8
JournalAnnals of Neurology
Volume42
Issue number4
DOIs
StatePublished - Oct 1997

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