Oxygen-derived free radicals have been implicated in the pathogenesis of vasogenic edema and infarction caused by ischeria and reperfusion injury. In earlier studies, exogenously supplied liposome-entrapped CuZn superoxide dismutase (CuZn-SOD) ameliorated ischemic brain edema and infarction in rats following focal cerebral ischemla. To ascertain directly the role of SOD in the protection against superoxide radical-induced injury, we measured infarct size and water content 24 hr following focal cerebral ischemia in nontransgenic mice and in transgeic mice bearing the human SODI gene. These transgenic mice have 3.1-fold higher cellular CuZn-SOD activity in the brain than do their nontransgenic littermates. We also'measured antioxidant levels (reduced glutathione and reduced ascorbate) of contralateral cortex, infarct cortex, surrounding cortex, and striatum. Infarct size and brain edema were s ntly decreased in trenic mice compared with nontransgenic mice. Reduced glutathione and reduced ascorbate levels decreased in the ischemlc hemisphere, -but levels-in surrounding cortex and striaturm were gficantly higher in trasgenic'mice than in nontransgenic mice. These rEsults indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the-pathogenesis of infarction and edema following focal cerebral ischemia.The role of oxygen free radicals in the pathogenesis of infarction and edema following cerebral ischemia has been intensively investigated since the report of Flamm et al. (1).Because of technical 4ffficulties in the measurement of free radicals'in brain tissues the part played by free radicals in the pathogenesis of cerebral ischemia still remains unclear (2, 3). However, reports of decreased levels of lipid-soluble and water-soluble endogenous antioxidants and of increased levels ofconjugated dienes and lipid peroxidation (4-10) support the notion that free radicals are involved in ischemic brain injury.Indirect methods using specific antioxidants [e.g., superoxide dismutase (SOD) and catalase] have traditionally been used to implicate oxygen free radicals in physiological or pathological processes. Unfortunately, the half-life of CuZn-SOD in circulating blood is extremely short (6 min), and it is unable to pass the blood-brain barrier. Therefore, use has been made of chemically modified enzymes for work on cerebral injury (11), and it has been found that polyethylene glycol-conjugated CuZn-SOD (PEG-SOD) and PEG-catalase reduce the degree of cortical infarction resulting from focal cerebral ischemia (12). Similarly, CuZn-SOD conjugated with divinyl ether/maleic acid copolymer ameliorated delayed hippocampal neuronal death after global cerebral ischemia in the gerbil brain (13). Liposome-entrapped CuZn-SOD, which has a half life of 4.2 hr (11), reduces the severity of traumatic and ischemic injuries (14,15).Although these studies provide potential therapeutic precedents for the management of brain in...
Abstract-The participation of polyamines and nonprotein sulfhydryls in the gastric cytoprotective mechanisms was studied using gastric mucosal lesions produced by acidified ethanol in rats as an experimental model. Treatment with prostaglandin E2 (PGE2), but not cimetidine, prevented the formation of gastric mucosal lesions. Oral administration of cadaverine, spermidine and spermine prevented the lesion formation by acidified ethanol in a dose-dependent manner. Indomethacin or acetazolamide had no influence on the cytoprotective effect of spermine , whereas sulfhydryl blockers such as iodoacetamide and N-ethylmaleimide partially blocked it. Sulfhydryl compounds such as cysteine, reduced glutathione (GSH), and cysteamine prevented the lesion formation induced by acidified ethanol. The concentration of nonprotein sulfhydryls in the gastric mucosa was significantly decreased at 1 hr after administration of acidified ethanol , and this decrease was partially prevented by spermine or PGE2. These results suggest that the cytoprotective effect of spermine may not be mediated by endogenous prostaglandins or alkaline secretion in the gastric mucosa, but may be partially related to endogenous sulfhydryl compounds.
Oxygen free radicals have been implicated in the pathogenesis of brain injury induced by ischemia/reperfusion. We studied the role of endogenous reduced glutathione (GSH) in brain infarction associated with focal cerebral ischemia caused by permanent ligation of the right middle cerebral artery (MCA) and the right common carotid artery (CCA) plus temporary occlusion of the left CCA. GSH levels in the ischemic side of cortex decreased with time after ischemia and preceded cortical infarction estimated by the staining of mitochondrial respiratory enzymes with 2,3,5-triphenyltetrazolium chloride. GSH levels in the contralateral cortex were unchanged through the experimental periods. The extent of decrease of GSH levels and the severity of infarction in the ischemic cortex at 24 h after ischemia depended on the duration of occlusion of the left CCA. Depletion of brain GSH with buthionine sulfoximine, a selective inhibitor for gamma-glutamylcysteine synthetase, exacerbated cortical infarction and edema after ischemia. These results suggest that the endogenous brain GSH is an important determinant in the defense mechanisms against lesion formation after ischemia and support the possible role of oxygen radicals in the pathogenesis of ischemic brain injury.
Abstract-The ileal Naϩ /bile acid cotransporter (IBAT) plays an important role in the enterohepatic circulation of bile acids. We investigated the effects of IBAT inhibition on the maintenance of serum cholesterol level by using a novel IBAT inhibitor, S-8921, in rabbits. Administration of S-8921 by its incorporation into the diet (0.01% to 0.1%) for 1 to 2 weeks in heterozygous Watanabe heritable hyperlipidemic rabbits decreased serum cholesterol by 29% to 37% and increased fecal excretion of measured bile acids by 60% to 180% compared with control rabbits. Liver microsomal cholesterol 7␣-hydroxylase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were increased by 75% to 84% and 84% to 89%, respectively, with S-8921 treatment. S-8921 administration (0.1% in the diet) to normal New Zealand White rabbits for 2 weeks resulted in increased hepatic low density lipoprotein receptor expression, which was assessed by Northern blot analysis. In cholesterol-fed New Zealand White rabbits, S-8921 treatment (0.003% to 0.1% in the diet) for 10 weeks dose-dependently inhibited the development of hypercholesterolemia. It also inhibited the accumulation of cholesterol in the aortic arch and reduced the severity of coronary atherosclerosis. These results indicate that IBAT inhibition by S-8921 affects serum cholesterol, liver enzymes, low density lipoprotein receptor activity, and atherosclerosis in the same manner as bile acid sequestrants. We suggest that an IBAT inhibitor such as S-8921 could be useful in the treatment of hypercholesterolemia. (Arterioscler Thromb Vasc Biol. 1998;18:1304-1311.) Key Words: ileal bile acid cotransporter Ⅲ serum cholesterol Ⅲ S-8921 Ⅲ LDL receptor Ⅲ cholesterol 7␣-hydroxylase H ypercholesterolemia has been recognized as a major risk factor for coronary heart disease (CHD). In clinical trials, reducing serum LDL cholesterol has been demonstrated to decrease the incidence of CHD and to reverse atherosclerotic lesions.1-4 Two main classes of clinically useful hypocholesterolemic agents are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the bile acid sequestrants. Both induce hepatic LDL receptor activity by increasing hepatic cholesterol demand. [5][6][7][8] Because the major determinant of serum cholesterol level is hepatic LDL receptor activity, 9 these agents share a common mechanism leading to reduction of cholesterol.In the case of bile acid sequestrants such as cholestyramine and colestipol, they are nonspecific anion-exchange resins, and patients have complained of their bulkiness. 10 The mechanism of action of a bile acid sequestrant is to inhibit the enterohepatic circulation of bile acids. Bile acids are synthesized from cholesterol in the liver and secreted into the bile flow to facilitate the digestion and absorption of lipids, followed by nearly quantitative reabsorption from the intestine. 11 The ileal Na ϩ /bile acid cotransporter (IBAT) maintains the reabsorption of bile acids from the intestine, 12,13 and thus, its inhibitor is expected...
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