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A Bcl‐2 antisense oligonucleotide increases α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) toxicity in cortical cultures
Author(s) -
White Melissa J.,
Chen Jun,
Li Zhu R.,
Irvin Stacy,
Sinor Amy,
DiCaprio Michael J.,
Jin Kunlin,
Greenberg David A.
Publication year - 1997
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410420408
Subject(s) - ampa receptor , toxicity , neurotoxicity , glutamate receptor , biology , pharmacology , chemistry , biochemistry , receptor , organic chemistry
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 accompained 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.