title: KR-31378 protects neurons from ischemia-reperfusion brain injury by attenuating lipid peroxidation and glutathione loss.
abstract: Neuronal hyperexcitability and oxidative stress play critical roles in neuronal cell death in stroke. Therefore, we studied the effects of (2S,3S,4R)-N?-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378), possessing both antioxidant and K(+) channel-modulating activities, on brain ischemia-reperfusion injury models. Treatment with KR-31378 (30 mg/kg, i.v.) significantly reduced infarct area and edema by 24% and 36%, respectively, in rats subjected to 2 h of middle cerebral artery occlusion and 22 h of reperfusion with significant attenuation of elevated lipid peroxidation (99% of normal) and glutathione loss (60% of normal) in ischemic hemisphere. We further studied its neuroprotective mechanism in fetal rat primary mixed cortical culture. Incubation of cortical neurons with KR-31378 protected FeSO(4)-induced cell death in a concentration-dependent manner (IC(50)=12 microM). Its neuroprotective effect was neither mimicked by other K(+) channel openers nor abolished in the presence of ATP-dependent K(+) channel (K(ATP)) blockers, indicating that its effect was not related to K(+) channel opening activity. The mechanism of protection is rather attributable to the antioxidant property of KR-31378 since it suppressed the intracellular accumulation of reactive oxygen species and ensured lipid peroxidation by 120% and 80%, respectively, caused by FeSO(4). We further studied its effect on antioxidant defense, enzymatic and nonenzymatic systems. Treatment of neurons with FeSO(4) resulted in decrease of catalase (8% of control) and glutathione peroxidase (14% of control) activities, which were restored by KR-31378 treatment (70% and 57% of control, respectively). In addition, it attenuated the depletion of glutathione contents (60% of control) caused by FeSO(4). These results suggest that KR-31378 exerts a beneficial effect in focal ischemia, which may be attributed to its antioxidant property.
authors.affiliation: Agropharma Research Institute, Dongbu Hannong Chemical Co., 103-2 Moonji-dong, Yusung, Daejeon 305-708, South Korea. sokim_99@msn.com
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: In Sun
authors.initials: IS
authors.lastname: Cho
authors.forename: Hee Kyoung
authors.initials: HK
authors.lastname: Gu
authors.forename: Dong Ha
authors.initials: DH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006146:Guanidines / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D007501:Iron / Q000037:antagonists & inhibitors / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D015221:Potassium Channels / Q000819:agonists*; D011714:Pyrans / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000975:Antioxidants; D005609:Free Radicals; D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D018696:Neuroprotective Agents; D015221:Potassium Channels; D011714:Pyrans; D007501:Iron; D005978:Glutathione