title: Polyphenol amentoflavone affords neuroprotection against neonatal hypoxic-ischemic brain damage via multiple mechanisms.
abstract: Flavonoids are naturally occurring polyphenolic compounds that have many biological properties, including antioxidative, anti-inflammatory and neuroprotective effects. Here, we report that amentoflavone significantly reduced cell death induced by staurosporine, etoposide and sodium nitroprusside in neuroblastoma SH-SY5Y cells. In post-natal day 7 rats, hypoxic-ischemic (H-I) brain damage induced by unilateral carotid ligation and hypoxia resulted in distinct features of neuronal cell death including apoptosis and necrosis. In this model, a systemic administration of amentoflavone (30 mg/kg) markedly reduced the H-I-induced brain tissue loss with a wide therapeutic time window up to 6 h after the onset of hypoxia. Amentoflavone blocked the activation of caspase 3, characteristic of apoptosis, and the proteolytic cleavage of its substrates following H-I injury. Amentoflavone also reduced the excitotoxic/necrotic cell death after H-I injury in vivo and after oxygen/glucose deprivation in mouse mixed cultures in vitro. Treatment of mouse microglial cells with amentoflavone resulted in a significant decrease in the lipopolysaccharide-induced production of nitric oxide and induction of inducible nitric oxide synthase and cyclo-oxygenase-2. Furthermore, amentoflavone decreased the inflammatory activation of microglia after H-I injury when assessed by the microglial-specific marker OX-42. These data demonstrate for the first time that amentoflavone strongly protects the neonatal brain from H-I injury by blocking multiple cellular events leading to brain damage.
authors.affiliation: Department of Manufacturing Pharmacy and Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Bae
authors.forename: Jeong Sook
authors.initials: JS
authors.lastname: Kim-Han
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: In Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Kun Ho
authors.initials: KH
authors.lastname: Son
authors.forename: Sam Sik
authors.initials: SS
authors.lastname: Kang
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Han
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D044946:Biflavonoids / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology; D002478:Cells, Cultured; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D002534:Hypoxia, Brain / Q000150:complications* / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D044946:Biflavonoids; D005419:Flavonoids; D018696:Neuroprotective Agents; D010636:Phenols; D059808:Polyphenols; C011164:amentoflavone