Oxidative stress is a mediator of cell death following cerebral ischemia/reperfusion and heme toxicity which can be an important pathogenic factor in acute brain injury. from delayed cell death. Exposure of immature hippocampal neurons to hemin induced significant cell death and both pre- and co-treatment with SFP were remarkably effective at blocking cytotoxicity. RT-PCR analysis indicated that several Nrf2-dependent cytoprotective genes including NAD(P)H quinone oxidoreductase 1 (NQO1) heme oxygenase 1 (HO1) and glutamate-cysteine ligase modifier subunit (GCLM) that is involved in glutathione biosynthesis were upregulated following SFP treatment both in control neurons and following exposure to OGD and hemin. These results indicate that SFP activates the ARE/Nrf2 pathway of antioxidant defense and protects immature neurons from death caused by stress paradigms relevant to those associated with ischemic and traumatic injury to the immature brain. studies exhibited the potential of SFP to protect against acute brain injury. In rodents SFP administered 15 minutes after stroke led to an increase in HO1 expression in brain and reduced infarct volume (Zhao et al. 2006 Post-injury administration of SFP also reduced brain edema following TBI in rats (Wang et al. 2007 Zhao et al. 2005 Although these studies indicate that SFP is usually a candidate for treatment of adult brain injury very little is known about the neuroprotective potential of SFP for immature brain injury. It is now well comprehended that developmental differences in energy metabolism glutamate excitotoxicity response to oxidative Rabbit polyclonal to AP1S1. stress and susceptibility to apoptosis distinguish the immature brain response to injury from that of the adult Pradaxa (Soane et al. 2008 Vannucci and Hagberg 2004 and that neuroprotective interventions should be optimized according to age. In addition the cellular site of action in the brain for electrophilic compounds like SFP that activate the ARE/Nrf2 pathway is not clear. Using an ARE reporter construct in mixed glial-neuron co-cultures a recent study indicated that activation of Nrf2 occurs predominantly in astrocytes and that neuroprotection was secondary to changes in glia (Kraft et al. 2004 Shih et al. 2003 Subsequent reports have challenged the notion that the protective effects of Nrf2 activation occur exclusively in astrocytes and indicated that mature neurons may also respond to Nrf2 activators through upregulation of ARE-responsive genes (Lee et al. 2003 Satoh et al. 2006 Whether this holds for immature neurons is not known. Therefore the potential of SFP to directly safeguard neurons against insults such as ischemia/reperfusion injury is still not clear. No studies have tested in neurons the protective potential of SFP against heme toxicity another clinically relevant oxidative stress paradigm that can mediate neuronal death following acute injury to both immature and mature brain (Bayir et al. 2006 Chang et al. 2005 Extravasation of Pradaxa blood in TBI or hemorrhagic stroke leads to the release of hemoglobin from red blood cells which in turn releases the iron-containing heme group (Platt and Nath 1998 Wagner et al. 2003 Following CNS hemorrhage free heme can reach high micromolar concentrations in the extracellular space (EC50 about 10 μM) and exert cytotoxic effects on both neurons and astrocytes (Chen-Roetling and Regan 2006 Goldstein et al. 2003 Heme and hemin (oxidized heme) are strong pro-oxidants and are normally metabolized by the heme oxygenase (HO) 1 and HO2 enzymes into biliverdin carbon monoxide and iron another pro-oxidant. Whether inhibiting Pradaxa or promoting heme catabolism is usually protective appears to be cell-type specific as genetic manipulation of the HO enzymes yielded opposing effects in neurons and astrocytes (Platt and Nath 1998 Wagner et al. 2003 Overexpression of HO1 guarded SN56 neuron-like cells from H2O2-induced death (Le Pradaxa et al. 1999 but PC12 Pradaxa cells cultured on HO1 overexpressing astrocytes were more prone to oxidative injury (Song et al. 2007 HO1 induction has been shown to protect astrocytes but not neurons from heme injury (Chen-Roetling and Regan 2006 while HO2 may be neuroprotective against intracerebral hemorrhage (Wang et al. 2006.