Polyphenol amentoflavone affords neuroprotection against neonatal hypoxic-ischemic brain damage via multiple mechanisms

J Neurochem. 2006 Jan;96(2):561-72. doi: 10.1111/j.1471-4159.2005.03582.x. Epub 2005 Dec 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn*
  • Anti-Inflammatory Agents / pharmacology*
  • Biflavonoids / pharmacology*
  • Brain / drug effects
  • Brain / pathology
  • Brain Damage, Chronic / etiology
  • Brain Damage, Chronic / prevention & control*
  • Brain Ischemia / complications*
  • Brain Ischemia / pathology
  • Cells, Cultured
  • Flavonoids / pharmacology
  • Humans
  • Hypoxia, Brain / complications*
  • Hypoxia, Brain / pathology
  • Mice
  • Microglia / drug effects
  • Neuroprotective Agents / pharmacology*
  • Phenols / pharmacology
  • Polyphenols
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Anti-Inflammatory Agents
  • Biflavonoids
  • Flavonoids
  • Neuroprotective Agents
  • Phenols
  • Polyphenols
  • amentoflavone