Twenty-four hour postischemic neuronal necrosis was compared in male vs. female Mongolian gerbils subjected to a 3-h period of severe incomplete hemispheric ischemia produced by unilateral carotid occlusion. The incidence of stroke-prone males was 42.9% versus 26.7% for the females. Among the stroke-prone animals, the males displayed significantly greater neuronal necrosis at 24 h after ischemia compared to the females in the cerebral cortex and CA1 region of the hippocampus. In the CA1 region of the stroke-prone males, only 2.0% of the normal neuronal population remained by 24 h compared to 36.8% in the stroke-prone females (p less than 0.02). In the cerebral cortex, the males had only 19.9% of normal versus 58.2% in the females (p less than 0.05). In a second series of mechanistic experiments, no differences in cortical blood flow (CBF) were disclosed between preselected male and female stroke-prone animals before, during, or for 2 h after ischemia. As with the CBF, the extent of cortical extracellular hypocalcia during ischemia did not differ significantly. However, the degree of postischemic recovery of cortical extracellular calcium was significantly better in the females from 30 min to 2 h after reperfusion. In the same experiments, hemispheric vitamin E levels were measured at the 2 h time point as an index of postischemic brain lipid peroxidation. No difference in baseline vitamin E levels was observed between male and female sham-operated gerbils. In the males subjected to 3 h of ischemia plus 2 h of reperfusion, the hemispheric vitamin E decreased by 43.5% compared to the sham-operated males.(ABSTRACT TRUNCATED AT 250 WORDS)

U74006F(21-[

We describe the effects of the 21-aminosteroid tirilazad mesylate (U-74006F) on postischemic lipid peroxidation (depletion of brain vitamin E) and cortical extracellular calcium recovery in gerbils subjected to 3 hours of unilateral carotid artery occlusion. Male gerbils were treated with either 0.2 ml vehicle (0.05N HC1) or 10 mg/kg i.p. U-74006F 10 minutes before the induction of ischemia and again immediately after the initiation of reperfusion. In the first series of experiments, the brain concentration of vitamin £, which was unaffected by ischemia without reperfusion, was decreased after 2 hours of reperfusion by an average of 60% in vehicle-treated animals compared with sham-operated animals; in the U-74006F-treated gerbils, the 2-hour postischemic vitamin £ loss was only 27% (p<0.002 different from vehicle-treated animals). In the second series, unilateral carotid artery occlusion produced a decrease in the cortical extracellular calcium concentration from 1.05 mM before ischemia to Received July 6, 1990; accepted November 7, 1990. inhibition of lipid peroxidation in vitro and its reduction of postischemic necrosis in vivo is circumstantial. We examined the effects of U-74006F on in vivo postischemic lipid peroxidation as assessed by attenuation of the depletion (i.e., utilization) of brain vitamin E following 3 hours of unilateral carotid artery occlusion in gerbils. In a parallel set of experiments, we studied the action of U-74006F on recovery from ischemia-induced cortical extracellular hypocalcia (i.e., intracellular calcium accumulation) 11 as an index of the compound's ability to preserve cell membrane function. Materials and MethodsIn the first series of experiments, male Mongolian gerbils weighing 55-65 g that had been fed and watered ad libitum were given either 10 mg/kg U-74006F or 0.Q5N HC1 vehicle (0.2 ml volumes) intraperitoneally 10 minutes prior to ischemia. After being lightly anesthetized with methoxyflurane, a 1-2-cm midline throat incision provided access to the right carotid artery, which was loosely encircled with by guest on May 12, 2018 http://stroke.ahajournals.org/ Downloaded from

The ability of the K-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-K close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA, neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i. considerable interest has developed concerning the possible role of endogenous opioids in ischemic pathophysiology and neuronal degeneration. Based on the anti-ischemic action of naloxone, an hypothesis has been developed that postischemic neuronal degeneration may in part depend on an excessive activation of endogenous opioid systems, which could be therapeutically antagonized with opiate receptor blocking drugs such as naloxone or naltrexone. However, some investigators have failed to observe a positive effect of naloxone in their particular ischemia models. 67 More recent studies have suggested that pharmacologic stimulation of the K-opiate receptor subtype can actually ameliorate rather than exacerbate postischemic neuronal degeneration and promote neurologic recovery and survival. The initial study in this regard showed that

Background and Purpose: The novel muscarinic cholinergic partial agonist U-80816E was tested in the gerbil brief bilateral carotid occlusion ischemia model based on the rationale that the compound's