Lipid peroxidation, model

A series of substituted diaryselenides were examined in three lipid peroxidation model systems isolated rat liver microsomes treated with Fe(II)/(ADP)/ascorbate and isolated rat hepatocytes treated with two different initiators of oxidation. In rat hepatocytes, all of the tellurides performed more effectively than the selenides. Particularly for the rat liver microsome system, the substituent effects on lipid peroxidation were consistent with what would be expected Electron-donating groups give more active compounds, while electron-withdrawing groups give poorer antioxidants. The same trends were seen for substituted diaryItellurides in inhibition of linoleic acid peroxidation in a two-phase model, where the dimethylamino... 

Mouse peritoneal macrophages that have been activated to produce nitric oxide by 7-interferon and lipopolysac-charide were shown to oxidize LDL less readily than unactivated macrophages. Inhibition of nitric oxide synthesis in the same model was shown to enhance LDL oxidation (Jessup etal., 1992 Yates a al., 1992). It has recently been demonstrated that nitric oxide is able to inhibit lipid peroxidation directly within LDL (Ho etal., 1993c). Nitric oxide probably reacts with the propagating peroxyl radicals thus terminating the chain of lipid peroxidation. The rate constant for the reaction between nitric oxide and peroxyl radicals has recently been determined to be 1-3 X10 M" s (Padmaja and Huie, 1993). This... 

At the present time it is difficult to single out any one factor that could be held ultimately responsible for cell death after cerebral ischaemia. Recent studies, however, have provided us with sufficient evidence to conclude that free radical damage is at least one component in a chain of events that leads to cell death in ischaemia/reperfiision injury. As noted earlier in this review, much of the evidence for free radicals in the brain and the sources of free radicals come from studies in animals subjected to cerebral ischaemia. Perhaps the best evidence for a role for free radicals or reactive oxygen species in cerebral ischaemia is derived from studies that demonstrate protective effects of antioxidants. Antioxidants and inhibitors of lipid peroxidation have been shown to have profound protective effects in models of cerebral ischaemia. Details of some of these studies will be mentioned later. Several reviews have been written on the role of oxygen radicals in cerebral ischaemia (Braughler and HaU, 1989 Hall and Btaughler, 1989 Kontos, 1989 Floyd, 1990 Nelson ef /., 1992 Panetta and Clemens, 1993). 

There is some support for a role for free radicals in the pathogenesis of ischaemic colitis from animal studies. Murthy and Qi (1992) used a spin trap to demonstrate increased production of free radicals up to 60 min after reperfusion, whereas Douglas etal. (1989) demonstrated increases in malondialdehyde and conjugated dienes (presumptive measures of lipid peroxidation) in a rat model of ischaemic colitis. There is no data relating to human ischaemic colitis. 

Furthermore, depletion of hepatic GSH induced chemically or by fasting augmented hepatic I/R-induced enzyme release and promoted lipid peroxidation (Jennische, 1984 Stein et al., 1991) Benoit et al. (1992) have used portacaval-shunted rats as a model of chronic hepatic ischaemia, and were able to show decreases in total levels of SOD and xanthine dehydrogenase, but no significant change in catalase or glutathione peroxidase. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

Carvediol is a vasodilator with beta-adrenergic antagonist activity. It has cardioprotective activity in animal models. The antioxidant effect of carvediol was compared with five other beta blockers in iron-initiated lipid peroxidation, where it inhibited TBARs formation and protected membrane-bound tocopherol in rat brain homogenate (Yue et al., 1992a). The ortJ <)-substituted phenoxylethyl-amine is responsible for the improved antioxidant activity. 

Idebenone, an inhibitor of lipid peroxidation, was shown to prolong survival time and delay the onset of ischaemic seizures in a bilateral carotid occlusion model in rats. It is marketed in Japan as a therapy to improve cerebral metabolism and performance after a stroke (Suno and Nagaoka, 1984). Cerebral protective effects after an ischaemic insult in dogs and rabbits have been seen with the hydroxyl radical scavenger, mannitol (Meyer et al., 1987). 

A series of dihydrodibenzoxepines, represented by AJ3941, was tested in animal models of global ischaemia and hypoxia, and found to be protective. AJ3941 is an inhibitor of lipid peroxidation (Kurakawa etal., 1991). A novel quinazoline fumarate (KB56666, was found to inhibit lipid peroxidation in rat brain homogenates and isolated mitochondria. In a rat focal stroke model, KE56666 prevented brain oedema and neuronal damage in the ischaemic zone (Hara etal., 1991). 

Ebselen is a seleno-oiganic that mimics glutathione peroxidase and inhibits iron-stimulated lipid peroxidation. It significandy reduced both inferct size and oedema progression in the middle cerebral artery exclusion (MCAO) focal model of stroke in tats (Matsui et al. 1990). Ebselen has also been shown to be an effective anti-inflammatory agent in a H202-dependent inflammation model in tats (Parnham 1991). 

Kassell (Takahashi et al., 1993) has described the activity of a novel tropolone U88999E in a rabbit model of cerebral vasosjrasm. U88999E inhibits lipid peroxidation and acts as a calcium antagonist. Kassell showed that the compound relaxed preconstricted arterial rings in vitro (potency slightly less than flunarizine or dil-tiazem) and that it reduced vasospasm of basilar arteries after rabbit subarachnoid haemorrhage (Takahashi etal., 1993). 

Chelators of transition metals like iron can remove free iron from the injury cascade. The iron chelator, desferri-oxamine, prevented the accumulation of lipid peroxides in 15 min cardiac arrest model in dogs followed by 2 h of resuscitation (Komara et al., 1986). 

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