Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat.
Cerebral ischemia followed by oxygen reperfusion induced apoptosis in hippocampal neurons in the stroke-prone spontaneously hypertensive rat (SHRSP) but not in Wistar Kyoto rats (WKY). We investigated whether 2-phenyl-1,2-benzisoselenazol-3(2H)-one, also called PZ51 (ebselen), useful for treating ischemic damage or antihypertension in the brain, can protect against ischemic neuronal damage in SHRSP. In this study, we compared the effects of ebselen, carvedilol, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) as well as vitamin E, added to cultures of neurons after reoxygenation (20% O(2)) following hypoxia (1% O(2)). SHRSP neurons died rapidly during reoxygenation following hypoxia but were rescued in large measure by 10 muM ebselen (neuronal death; 2.7+/-1.4%). In order of neuroprotective potency, the agents ranked as follows: ebselen>carvedilol>MCI-186>vitamin E. In vivo, strong neuroprotection by ebselen was observed in the hippocampal CA1 region of SHRSP (32.9+/-9.5 apoptotic neuron/1000 neurons, 30 mg/kg/day). Ebselen prevented apoptosis as confirmed by morphological observations in vivo. Its effect was associated with the expression of Bcl-2 and Bax. These findings suggest that ebselen has a marked inhibitory effect on neuronal damage during stroke. Ebselen may be effective in the prevention and/or treatment of neurodegenerative diseases associated with excessive apoptosis in patients with stroke.
Yamagata
K
K
Department of Food Science and Technology, College of Bioresource Sciences, Nihon University, Fujisawa-shi, Kanagawa-ken, Japan. kyamagat@brs.nihon-u.ac.jp
Ichinose
S
S
Miyashita
A
A
Tagami
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy*; D054833:Isoindoles; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016566:Organoselenium Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D000975:Antioxidants; D001393:Azoles; D018076:DNA, Complementary; D054833:Isoindoles; D016566:Organoselenium Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C042986:ebselen; D012313:RNA; D007770:L-Lactate Dehydrogenase