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, hypoxicischemic (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.

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

“…Flavanols (e.g., epicatechin (EC) and catechin) and their monomers/oligomers/polymers, known as procyanidins, compose a major category of secondary polyphenolic plant metabolites. Mounting evidence suggests a protective role for various polyphenols and flavonoids in cerebral ischemia (Lee et al, 2004;Lee et al, 2000;Shah et al, 2005;Shin et al, 2006;Simonyi et al, 2005). It is noteworthy also that flavanols have been shown to improve vasorelaxation (Duarte et al, 1993;Karim et al, 2000).…”

Ischemic Preconditioning Reduces Neurovascular Damage After Hypoxia-Ischemia Via the Cellular Inhibitor of Apoptosis 1 in Neonatal Brain

“…SH-SY5Y has been commonly used to study the neural cell survival in the developing brain. 26 HMEC-l that displays the same morphologic, phenotypic, and functional characteristics as the normal HMECs also has been used as an in vitro model for blood-brain barrier damage. 27 Although primary neuronal and endothelial cells may have a limited lifespan, further study using these cells should be performed to examine the role of cIAP1 in preconditioningmediated neurovascular protection against OGD.…”

Pomegranate Polyphenols and Resveratrol Protect the Neonatal Brain against Hypoxic-Ischemic Injury

“…5 a). We also tested if 20 mg/kg of resveratrol is protective when administered 3 h after the injury since the time course of caspase-3 activation is different between rats and mice and since there has been reports of neuroprotective agents working in the rat when administered after the injury [Wei et al, 2004;Shin et al, 2006]. However, at this time point, resveratrol is not protective against caspase-3 activation ( fig.…”