Effects of tirilazad mesylate on postischemic brain lipid peroxidation and recovery of extracellular calcium in gerbils.

Abstract

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

Tirilazad reduces cortical infarction after transient but not permanent focal cerebral ischemia in rats.

“…30 Vitamin E content was not affected by 3 hours of permanent ischemia; however, 2 hours after reperfusion, vitamin E levels fell by 60% in vehicle-treated gerbils compared with only 27% in those treated with U74006F. The vitamin E levels were measured before histological injury was apparent, suggesting that the decrease in vitamin E reflects a critical event in ischemic pathogenesis rather than simply a correlation with tissue degeneration.…”

“…The vitamin E levels were measured before histological injury was apparent, suggesting that the decrease in vitamin E reflects a critical event in ischemic pathogenesis rather than simply a correlation with tissue degeneration. 30 The reduction in the peroxide product malonaldehyde in subarachnoid clots with U74006F is also indicative of its ability to inhibit lipid peroxidation in vivo. 31 Although the beneficial effects of U74006F may be vascular rather than parenchymal, given its ability to inhibit vitamin E loss 30 we suggest that U74006F reduces the infarct volume in transient ischemia through its ability to inhibit lipid peroxidation during reperfusion.…”

“…30 The reduction in the peroxide product malonaldehyde in subarachnoid clots with U74006F is also indicative of its ability to inhibit lipid peroxidation in vivo. 31 Although the beneficial effects of U74006F may be vascular rather than parenchymal, given its ability to inhibit vitamin E loss 30 we suggest that U74006F reduces the infarct volume in transient ischemia through its ability to inhibit lipid peroxidation during reperfusion. 7 - 8 Without direct measurement of lipid peroxidation products, however, this conjecture remains debatable.…”

Combination Therapy with Neuroprotectants and Thrombolytics in Acute Ischaemic Stroke

“…These mechanisms can be blocked by tirilazad mesylate [38,39]. Though cardiotoxicity occurred with tirilazad mesylate in dog experiments, it was no more common in patients treated with a dose limited to 6.0 mg/kg/day for 3 days than in those receiving placebo [40].…”

Effect of Early Treatment with Tirilazad (U74006F) Combined with Delayed Thrombolytic Therapy in Rat Embolic Stroke

“…The 21-aminosteroids developed by Braughler et al [15], Hall and Yonkers [16], and McCall et al [17] interact with the cell membrane and inhibit lipid peroxidation by reacting with hydroxyl radicals and lipid peroxides. During or following cerebral ischemia, inhibi tion of lipid peroxidation may lead to a reduced break down of triglycerides and stabilization of transmembranous ion gradients [18,19], and these processes may be of importance in acute ischemic stroke, since spontaneous recanalization [20] and reperfusion [21] are common phe nomena during the initial development of an ischemic lesion in the hum an brain. Thrombolytic therapy is one approach to restore blood flow in ischemic areas, and this treatm ent has been tested in several open clinical trials in hum an acute ischemic stroke [22], However, the data from experimental [14,[23][24][25][26][27][28][29] and clinical studies [30,31] indicate that thrombolytic therapy alone cannot pre vent the development of an ischemic lesion.…”