Transient global ischemia results in delayed selective neuronal death
of hippocampal CAI pyramidal cells. Glucocorticoids increase and adren
alectomy decreases the rate of neuronal death; however, they also prod
uce changes in brain temperature, serum glucose and adrenocorticotropi
c hormone levels. In order to understand the role of glucocorticoids i
n regulating ischemic cell death, we studied RU 38486, a glucocorticoi
d receptor blocker, and Org 2766, a non-steroidogenic adrenocorticotro
pic hormone 4-9 analog. Male Mongolian gerbils were subjected to 5 min
of bilateral carotid artery occlusion under a controlled temperature
environment (37.0-38.0 degrees C). Animals were injected with either p
hysiological saline, Org 2766 (10 mu g/kg/24 h) or RU 38486 (50 mg/kg/
8 h), beginning just prior to the occlusion until killing at either da
y 4 or 7. Blood was collected for serum glucose and cortisol analysis.
Damage was evaluated by blinded counts of CA1 neurons. Both RU 38486
and Org 2766 treatment significantly (P<0.004) reduced hippocampal CA1
damage at day 4; but not on day 7. While RU 38486 raised serum cortis
ol and adrenocorticotropic hormone levels, neither treatment affected
temperature or serum glucose. The fact that RU 38486 mimicked adrenale
ctomy without changing temperature suggests that the decreased rate of
cell death resulted from either removal of glucocorticoids or increas
es in adrenocorticotropic hormone. The ability of Org 2766 to affect t
his rate strongly suggests that adrenocorticotropic hormone is the act
ive regulatory hormone rather than glucocorticoids. While both RU 3848
6 and Org 2766 prolong the survival of CA1 neurons after transient glo
bal ischemia, only RU 38486, which is available and tested in both ani
mals and humans, can block the detrimental effects of post-ischemia gl
ucocorticoid elevations. Thus, the administration of RU 38486 may be a
practical adjunct to other neuroprotective agents for victims of card
iac arrest, anesthetic accidents or drowning. (C) 1998 IBRO. Published
by Elsevier Science Ltd.