It has been reported that selective neuronal loss of dentate gyrus (DG) granule cells develops 3 to 4 months after adrenalectomy (ADX) in rats, which can be suppressed by replacement of corticosterone (CORT). In previous studies, rats were given saline after ADX to prevent hyponatremia and death. In clinical practice, adrenal insufficiency is often accompanied by hyponatremia. However, whether hyponatremia affects the cell injury associated with adrenal insufficiency remains to be elucidated. Thus, in the present study, we developed a rat model of hyponatremia accompanied by adrenal insufficiency and examined the effects of hyponatremia on cells including neurons. Rat model of hyponatremia accompanied by adrenal insufficiency was developed by administration of low sodium-liquid diet after bilateral ADX. Apoptosis, neurodegenerative cells and neurogenesis were evaluated by immunohistochemistry using ApopTag, Fluoro-Jade C and doublecortin antibody, respectively. Moderate or severe hyponatremia was induced on the 7th day after ADX. All rats that were given CORT and saline on the 7th day survived. Selective apoptosis of DG granule cells in hyponatremic rats was observed as early as on the 9th day, regardless of the presence or absence of the treatment of CORT and saline. On the other hand, no normonatremic rats showed apoptosis in DG. In addition, activation of microglia and astrocyte, and enhancement of neurogenesis in the subgranular zone (SGZ) were observed on the 8th as well as 9th day. Our results demonstrate that the treatment of CORT and saline against moderate or severe hyponatremia accompanied by adrenal insufficiency could rescue rats from death, however, the treatment could not rescue the selective apoptosis of DG granule cells. Further examination is needed to clarify the mechanism of the apoptosis and possible role of activation of microglia and astrocyte, and enhancement of neurogenesis in the SGZ before the apoptosis occurs.