Disease relevance of U 74006

• Protective effect of the lazaroid U74006F in cold ischemia-reperfusion injury of the liver [1].
• Effect of U74006F on forebrain ischemia in rats [2].
• Pretreatment with U74006F improves neurologic outcome following complete cerebral ischemia in dogs [3].
• Effect of high-dose methylprednisolone and U74006F on eicosanoid synthesis after subarachnoid hemorrhage in rats [4].
• Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in dogs [5].

High impact information on U 74006

• The lazaroid compound U74006F is a potent inhibitor of lipid peroxidation, and this study was designed to evaluate the efficacy of this compound in preventing cold ischemia-reperfusion damage in three different models: pig endothelial cells in culture, ex vivo isolated pig liver perfusion and orthotopic transplantation of syngeneic rat livers [1].
• The addition of U74006F to University of Wisconsin preservation solution significantly prolonged endothelial cell viability after 48 and 72 hr of cold ischemia and reoxygenation (p < 0.01) [1].
• Treatment with either 100 microM U-74006F or 1 microM U-101033E resulted in a right-hand shift (protection) in the peroxynitrite toxicity curve [6].
• Vehicle-treated animals exposed to 15 min of ischemia sustained 60 +/- 35% (n = 16) CA1 pyramidal cell necrosis whereas U74006F-treated animals lost 61 +/- 30% (3 mg/kg, n = 9), 42 +/- 35% (10 mg/kg, n = 15), 62 +/- 28% (5 x 10 mg/kg, n = 10), and 74 +/- 30% (8 x 10 mg/kg, n = 10) of CA1 pyramidal cells [7].
• For animals suffering 5 min of transient forebrain ischemia, vehicle-treated rats lost 19 +/- 26% (n = 14), whereas U74006F-treated (8 x 10 mg/kg) animals lost 36 +/- 39% (n = 15) of CA1 neurons [7].

Chemical compound and disease context of U 74006

• We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery [8].
• We designed this study to determine whether the aminosteroid U74006F, a putative inhibitor of lipid peroxidation, mitigates cerebral multifocal hypoperfusion after cardiac arrest [5].
• In contrast, the same doses of U74006F (1.0, 3.0, and 10 mg/kg) that attenuated posttraumatic ischemia also significantly reduced the depletion of cord vitamin E. The lowest U74006F dosage (0.3 mg/kg), which failed to affect posttraumatic ischemia development, also had no effect on spinal cord vitamin E content.(ABSTRACT TRUNCATED AT 250 WORDS)[9]
• Only one (5.2%) of 19 rats receiving high-dose U74006F (10 mg/kg) died within 72 hours after ischemia, compared with five deaths (29.4%) in 17 rats receiving citrate vehicle alone (p = 0.060) [10].
• It is hypothesized that reperfusion injury accompanies renal ischemia, and postischemic administration of one of these steroids, U74006F, will reduce renal damage in a rodent model, as assessed by renal function (plasma creatinine), histologic evidence of renal injury, and animal survival during a 72-hour interval [10].

Biological context of U 74006

• U74006F had no effect on cortical blood flow, somatosensory evoked potentials, or blood pressure in nonischemic cats [11].
• We conclude that treatment with U74006F after prolonged cardiac arrest causes no deleterious side effects and does not seem to alter multifocal postarrest cerebral blood flow and oxygen consumption [5].
• We tested the hypothesis that the 21-aminosteroid tirilazad mesylate (U74006F), an inhibitor of lipid peroxidation in vitro, ameliorates somatosensory evoked potential recovery and acidosis during reperfusion after severe incomplete cerebral ischemia [12].
• The capillary permeability after subarachnoid injection of blood was normalized by pretreatment with a novel 21-aminosteroid, U-74006F, that has antioxidant and antilipolytic activity [13].
• U-74006F treatment did not affect the extent of complement activation during reperfusion, the Kupffer cell-induced oxidant stress, or tumor necrosis factor-alpha formation in this model [14].

Anatomical context of U 74006

• We investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats [15].
• However, both the acute and sustained U74006F treatments produced a significant reduction in the severity of neuronal damage in the neocortex (p less than 0.05) [2].
• Two 21-aminosteroids (U-74500A and U74006F) were shown to preferentially alter the fluorescence anisotropy and lifetime parameters of the diphenylhexatriene probe distributing into membranes throughout the BMECs [16].
• We conclude that damage to membrane lipids by peroxidative and/or lipolytic processes is involved in the subarachnoid hemorrhage-induced blood-brain barrier opening and that U-74006F protects the blood-brain barrier against the effects of subarachnoid hemorrhage by preventing or limiting these pathologic membrane lipid changes [13].
• In the second series, unilateral carotid artery occlusion produced a decrease in the cortical extracellular calcium concentration from 1.05 mM before ischemia to 0.11 mM by the end of the ischemic episode in both vehicle- and U-74006F-treated gerbils [17].

Associations of U 74006 with other chemical compounds

• However, these data suggest that the antioxidant effect of single-dose treatment with U74006F influenced the early and delayed effects on enzymatic lipid peroxidation, whereas the effects of methylprednisolone administration every 8 hours were more significant in the delayed phase [4].
• Selected 21-aminosteroids (U74500A, U74006F, and U74389G) and a 2-(aminomethyl)chromans (U78517F) were tested for their efficacy in preventing arachidonate-induced lipid peroxidation and permeability alterations in brain microvessel endothelial cells (BMECs) [18].
• U78517F inhibited 200 microM FeCl2-initiated lipid peroxidation in rat brain homogenates by 50% at a concentration of 0.6 microM compared with 8 microM for U74006F, 28 microM for alpha-tocopherol, and 43 microM for the ring portion of alpha-tocopherol (i.e., trolox) [19].
• The results indicate that U-74006F inhibits postischemic lipid peroxidation as assessed by the preservation of brain vitamin E and that, secondary to this membrane-protective effect, the processes responsible for the reversal of ischemia-triggered intracellular calcium accumulation are preserved [17].
• Administration of the 21-aminosteroid inhibitor of lipid peroxidation, tirilazad mesylate (U74006F), prevented the decrease in level of both of these vitamins following 2 h of reperfusion [20].

Gene context of U 74006

• Their IC(50) ranged from 10(-3) M to 10(-6) M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A [21].
• U78517F is a novel inhibitor of iron-catalyzed lipid peroxidation that combines the tetramethylchroman antioxidant ring portion of alpha-tocopherol with the amine of the previously described 21-aminosteroids (e.g., U74006F) [19].
• Antioxidant lazaroid U-74006F improves renal function and reduces the expression of cytokines, inducible nitric oxide synthase, and MHC antigens in a syngeneic renal transplant model. Partial support for the response-to-injury hypothesis [22].
• In conclusion, survival of TH-positive neurons is enhanced by U-74006F, which is readily available for clinical use and thus could be employed to enhance graft survival when transplanting patients suffering from Parkinson's disease [23].
• U74006F-treated animals had significantly reduced MPO activity (60% lower) when compared with vehicle-treated animals at the end of the second and third weeks [24].

Analytical, diagnostic and therapeutic context of U 74006

• Although bile production was similar in the U74006F-treated and control groups, significant decreases of AST and ALT levels (p < 0.01) in the perfusate of the livers from treated donors were observed [1].
• A treatment group (n = 5) received U74006F starting with reperfusion (1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose 4.5, 7.5, or 14.5 mg/kg) [5].
• Male Mongolian gerbils received two intraperitoneal injections of either vehicle or U74006F (3 or 10 mg/kg), the first injection 10 minutes before and the second injection at the end of the 3-hour ischemic episode [25].
• One of these, U74006F or tirilazed mesylate, has been shown to be effective in animal models of brain and spinal cord injury and is currently undergoing phase II clinical trials [26].
• Pretreatment of 0.3 microM U-74006F during dissection combined with intraocular injections of U-74006F after grafting, on the other hand, resulted in a dose-dependent enhancement of survival of TH-positive neurons [23].

References