THE ROLE OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN TRANSIENT FOREBRAIN ISCHEMIA IN THE RAT-BRAIN

BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) may play a role in the pathophysiology of neuronal cell death after cerebral ischemia. We investigated alterations in BDNF gene expression and the effect of BDNF on neuronal death after transient forebrain ischemia in the rat brain. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries and by producing systemic hypotension for 8 minutes. The alterations in the BDNF messenger ribonucleic acid content in the hippocampus and the cerebral cortex were examined by Northern blot analysis, using a phosphorus-32-labeled mouse BDNF complementary deoxyribonucleic acid probe. Recombinant Chinese hamster ovary cells with BDNF-secreting capacity were established by expression vector transfection with BDNF complementary deoxyribonucleic acid. The effect of BDNF on neuronal death in the hippocampal CA1 region after ischemia was then examined by using a continuous intraventricular infusion of 200 mu l of normal (Group II, n = 6) or 30-times concentrated recombinant Chinese hamster ovary cell culture medium containing BDNF (Group IV, n = 6). Normal (Group I, n = 6) or 30-times concentrated (Group III, n = 6) Chinese hamster ovary cell culture medium, not including BDNF complementary deoxyribonucleic acid, was infused into the same ischemic brains, which served as controls. Northern blot analysis showed that the amounts of BDNF messenger ribonucleic acid of two different lengths (1.5 Kb and 4.2 Kb) in the hippocampus increased rapidly, reached a maximum in 2 hours, and returned to the normal level 12 hours after transient forebrain ischemia, whereas, in the cerebral cortex, the level of BDNF messenger ribonucleic acid increased more slowly, with the peak occurring 6 hours after the ischemia. Cell death in the hippocampal CA1 region 7 days after the ischemia was 22% +/- 8% (mean +/- SD, n = 6) of the total CA1 neurons in Group I; 27% +/- 8% (mean +/- SD, n = 6) in Group II; 22% +/- 5% (mean +/- SD, n = 6) in Group III; and 1% +/- 1% (mean +/- SD, n = 6) in Group IV. These results suggested that BDNF gene expression was enhanced by transient ischemia both in the hippocampus and in the cerebral cortex and that BDNF, at a sufficient dose, has a preventive effect on the delayed hippocampal neuronal death observed after transient forebrain ischemia.