PubMed · 3147921
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S C Gad. 1988. Standard mouse ear swelling test (MEST). https://doi.org/10.1016/0272-0590(88)90138-8
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A possible protective effect of a novel free radical scavenger, OPC-14117, on the progressive motor neuron death in wobbler mice was examined. Clinical parameters such as mortality, body weight, motor activity as a rolling number of circular cage, and forelimb muscle power as grasping on a rolling column, an angle of slipping down from slope, and hanging ability on a flat plate were compared every 4 weeks from 4 to 36 weeks of age among mice groups treated with vehicle or daily oral administration of OPC-14117 of 10 or 30 mg/kg body weight. The treatment with OPC-14117 dose dependently improved the clinical parameters such as mortality, motor activity, and forelimb weakness. Pathological analysis showed that a diffuse neurogenic change in the forelimb muscle was improved at 36 weeks of age in the drug treated mice with a marked preservation of motor neurons in the spinal cord. Treatment of the mice with the drug reduced age-dependent increase of lipid peroxides in the spinal cord in vivo, and a supplement of the drug to the homogenate of spinal cord in vitro ameliorated the formations of lipid peroxides generated by an exogenous addition of ascorbate or xanthine/xanthine oxidase. These results suggest that OPC-14117 has a protective effect on the motor neuron death probably as a free radical scavenger, resulting in an improvement of clinical symptoms in wobbler mice.
Doxorubicin (DOX)-induced cardiotoxicity is thought to be caused by free radical-mediated mechanisms. An in vivo rat model was developed to investigate the DOX-induced cascade of early biochemical changes focusing on the central role of the aldehydic lipid peroxidation products. Antioxidant status was evaluated by glutathione measurements. Creatine Kinase (CK) activity was measured as an index of cardiac injury. Development of functional abnormalities were documented by echocardiography. The results showed that aldehydes in rat plasma and heart tissues increased significantly following DOX treatment. The changes occurred early, peaked around 2 h after DOX administration, and the levels declined or returned to baseline value within 8-24 h. Toxic aldehyde levels including malondialdehyde, hexanal and 4-hydroxy-non-2-enal also increased. Acyloin levels, metabolic products of aldehydes, increased early and then decreased in plasma, and there was a significant decrease in heart tissues after DOX treatment. GSH levels decreased early, then increased by 24 h, while GSSG levels decreased initially, then increased after DOX treatment, suggesting early depletion of GSH and a later rebound phenomenon. CK levels were elevated after treatment. The functional abnormalities were documented by stress echocardiography in some rats although the changes were not consistent at such an early stage following treatment. Our data confirmed the involvement of free radicals, and suggested that the cytotoxic aldehydes play a central role in initiating the steps that lead to functional impairment of the myocardium following DOX administration. Scavengers and the metabolic removal of some of the aldehydes also play a role in protecting the myocardium against injury.
Malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are major end-products of oxidation of polyunsaturated fatty acids, and are frequently measured as indicators of lipid peroxidation and oxidative stress in vivo. MDA forms Schiff-base adducts with lysine residues and cross-links proteins in vitro; HNE also reacts with lysines, primarily via a Michael addition reaction. We have developed methods using NaBH4 reduction to stabilize these adducts to conditions used for acid hydrolysis of protein, and have prepared reduced forms of lysine-MDA [3-(N epsilon-lysino)propan-1-ol (LM)], the lysine-MDA-lysine iminopropene cross-link [1,3-di(N epsilon-lysino)propane (LML)] and lysine-HNE [3-(N epsilon-lysino)-4-hydroxynonan-l-ol (LHNE)]. Gas chromatography/MS assays have been developed for quantification of the reduced compounds in protein. RNase incubated with MDA or HNE was used as a model for quantification of the adducts by gas chromatography/MS. There was excellent agreement between measurement of MDA bound to RNase as LM and LML, and as thiobarbituric acid-MDA adducts measured by HPLC; these adducts accounted for 70-80% of total lysine loss during the reaction with MDA. LM and LML (0.002-0.12 mmol/ mol of lysine) were also found in freshly isolated low-density lipoprotein (LDL) from healthy subjects. LHNE was measured in RNase treated with HNE, but was not detectable in native LDL. LM, LML and LHNE increased in concert with the formation of conjugated dienes during the copper-catalysed oxidation of LDL, but accounted for modification of < 1% of lysine residues in oxidized LDL. These results are the first report of direct chemical measurement of MDA and HNE adducts to lysine residues in LDL. LM, LML and LHNE should be useful as biomarkers of lipid peroxidative modification of protein and of oxidative stress in vitro and in vivo.