title: Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats.
abstract: Nobiletin, a citrus polymethoxylated flavone, is reported to possess various pharmacological activities such as anticancer, anti-inflammation, and antioxidant effects. Recently, nobiletin was shown to provide therapeutic benefit for the treatment of Alzheimer׳s disease by activating cAMP-response element-binding protein (CREB). In the present study, we investigated whether nobiletin could protect the brain against ischemia-reperfusion (I/R) injury and improve functional outcome in cerebral I/R model rats, since CREB activation is known to protect neuronal cells in cerebral ischemia. Nobiletin was injected twice at 0 and 1h after the start of reperfusion in transient middle cerebral artery occlusion (t-MCAO) rats. Cerebral I/R induced prominent brain damage in the ischemic hemisphere of t-MCAO rat brains; however, nobiletin treatment significantly reduced the infarct volume and suppressed the brain edema. Immunohistochemical and TUNEL staining indicated that nobiletin treatment significantly suppressed neutrophil invasion into the ischemic region and significantly decreased apoptotic brain cell death in ischemic hemisphere, suggesting that the anti-inflammatory effect and anti-apoptotic effect should be regarded as the neuroprotective mechanism of nobiletin. Moreover, nobiletin treatment ameliorated motor functional deficits in the ischemic rats compared with those deficits of the vehicle-treated group. These results indicate that nobiletin is a potential neuroprotectant for the treatment of cerebral I/R injury.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Nodoka
authors.initials: N
authors.lastname: Yasuda
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Oyama
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukuta
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Agato
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Synthetic Organic and Medicinal Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asakawa
authors.affiliation: Department of Synthetic Organic and Medicinal Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kan
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Department of Anti-dementia Functional Food Development, Graduate School of Engineering, Tohoku University, Sendai, Japan; Yokohama College of Pharmacy, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohizumi
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D047309:Flavones / Q000493:pharmacokinetics / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047309:Flavones; D018696:Neuroprotective Agents; C008661:nobiletin
keywords: Citrus polymethoxylated flavone; Ischemic stroke; Motor function deficit; Neuroprotectant; Neutrophil infiltration; Nobiletin