title: Ibudilast, a phosphodiesterase inhibitor with anti-inflammatory activity, protects against ischemic brain injury in rats.
abstract: Ibudilast, a non-selective phosphodiesterase inhibitor, is clinically used in patients with stroke or dizziness. However, whether the compound exerts a beneficial effect on acute ischemic stroke remains to be established. We used a rat model of transient focal cerebral ischemia using middle cerebral artery occlusion (MCAO) and reperfusion, and explored the effects of ibudilast on infarction size, brain edema, atrophy, and nerve cell death. Neurological outcomes (behavior and mortality) of rats were also assessed. An intravenous administration of ibudilast attenuated the size of cerebral infarction in a dose-dependent manner, with the most significant reduction achieved at the dose of 10mg/kg. Ibudilast induced a significant reduction in infarct size when administered 30min before MCAO or 0-2h after reperfusion, with the largest reduction observed at 30min before MCAO and 1h after reperfusion. Ibudilast significantly attenuated brain edema formation, cerebral atrophy and apoptosis of nerve cells preferentially in the cortical penumbra area, and also significantly reduced mortality and improved neurological outcomes. Expression of various inflammatory mediator molecules in both hemispheres was markedly suppressed by ibudilast. We conclude that ibudilast exerts beneficial effects against acute brain ischemia in an animal model.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. jlee@amc.seoul.kr
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Eunsil
authors.initials: E
authors.lastname: Cho
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Ko
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Sun U
authors.initials: SU
authors.lastname: Kwon
authors.forename: Dong-Wha
authors.initials: DW
authors.lastname: Kang
authors.forename: Jong S
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D020520:Brain Infarction / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009460:Neurologic Examination; D009474:Neurons / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013997:Time Factors; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D009419:Nerve Tissue Proteins; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles