l-683590 and domoic-acid

Although pathogenesis of neuronal ischemia is incompletely understood, evidence indicates apoptotic neuronal death after ischemia. Bcl-2, an anti-apoptotic and neuroprotective protein, interacts with calcineurin in non-neuronal tissues. Activation of calcineurin, which is abundant in the brain, may play a role in apoptosis. Using co-immunoprecipitation experiments in biopsy-derived, fresh human cortical and hippocampal slices, we examined possible interactions between calcineurin and Bcl-2. Calcineuin-Bcl-2 interactions increased after exposure in vitro to excitotoxic agents and conditions of hypoxia/aglycia. This interaction may shuttle calcineurin to substrates such as the inositol-1,4,5-tris-phosphate receptor because under these experimental conditions interactions between calcineurin and inositol-1,4,5-tris-phosphate receptor also increased. A specific calcineurin inhibitor, FK-520, attenuated insult-induced increases in calcineurin-Bcl-2 interactions and augmented caspase-3 like activity. These data suggest that Bcl-2 modulates neuroprotective effects of calcineurin and that calcineurin inhibitors increase ischemic neuronal damage.

Topics: Adult; Blotting, Western; Calcineurin; Calcium Channels; Caspase 3; Caspases; Cerebral Cortex; Enzyme Inhibitors; Enzyme Precursors; Female; Humans; Hypoxia, Brain; Immunosuppressive Agents; In Vitro Techniques; Inositol 1,4,5-Trisphosphate Receptors; Kainic Acid; Male; Middle Aged; N-Methylaspartate; Neurotoxins; Okadaic Acid; Precipitin Tests; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; Spectrin; Tacrolimus