An
immunosuppressant tacrolimus (
FK506) protects against neuronal damage following
cerebral ischemia. On the other hand, the major physiological role of the
immunophilin FK506-binding protein-12 (
FKBP12) is a modulation of intracellular
calcium flux. Since an increase in intracellular
calcium concentration is a major mediator of ischemic neuronal death, we investigated the changes in
FKBP12 following
cerebral ischemia in the rat. We induced focal
cerebral ischemia by intraluminal occlusion of the middle cerebral artery for 1 h, and global
cerebral ischemia for 10 min by bilateral carotid artery occlusion combined with
hypotension. The animals were killed at 4 h to 7 days after reperfusion. Immunohistochemistry was performed on
paraffin sections using a
monoclonal antibody raised against recombinant
FKBP12. Immunoreactivity to
FKBP12 in control brains was most pronounced in the CA1 subfield of the hippocampus and the striatum, the localization being primarily neuronal. Following focal
ischemia,
FKBP12 immunoreactivity decreased rapidly in the ischemic core by 4 h, but increased in surviving neurons in penumbra areas (4
h-7 days). Within an area of
infarction, invading leukocytes and macrophages exhibited immunoreactivity to
FKBP12 (3-7 days). Following global
ischemia,
FKBP12 immunoreactivity in CA1 neurons decreased after 1 day, and then it was lost between 2 and 7 days, although many CA1 neurons showed a transient increase in
FKBP12 at 2 days. No
FKBP12 immunoreactivity was observed in reactive glial cells. Thus,
FKBP12 declined in dying neurons, whereas
FKBP12 was upregulated in less severely injured neurons. The findings suggest that (1)
FKBP12 plays an important role in the process of neuronal survival and death following
cerebral ischemia, and (2)
FKBP12 is involved in inflammatory reactions that occur within an area of
infarction.