REGULATION OF ISCHEMIC CELL-DEATH BY GLUCOCORTICOIDS AND ADRENOCORTICOTROPIC HORMONE

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.