Effects of long-term adrenalectomy on apoptosis and neuroprotection in the rat hippocampus.
Reduction in corticosterone by acute adrenalectomy (5 d) promotes apoptosis in dentate gyrus (DG) granular neurons, an effect concomitant with variations in the expression of the Bcl-2 gene family implicated in apoptotic regulation. However, no studies exist correlating the effect of long-term adrenalectomy (30 d) on the hippocampus in terms of extent of apoptosis and the levels of proteins related to an apoptotic cascade. After 5 d of adrenalectomy, we found an increase in apoptosis of the DG granular region, correlated with an increase in the processing of caspase-9. The magnitude of apoptosis 30 d after adrenalectomy was reduced in the DG granular layer compared with 5 d after adrenalectomy, in close relation to a reduction in the level of processed caspase-9. To understand how the increase in cell survival long after adrenalectomy occurs, we analyzed changes in the expression of genes and proteins related to apoptosis. Long-term adrenalectomy did not change hippocampal pro-apoptotic Bax or antiapoptotic Bcl-2 mRNA levels or protein content with respect to control. However, we found an increase in mRNA levels of the GD's Bcl-x gene, in parallel with the increase in anti-apoptotic BCL-XL protein levels. These results suggest the reduction in apoptosis observed after long-term adrenalectomy occurs through mechanisms that repress proapoptotic genes previously found to be increased at shorter times of adrenalectomy.