br Introduction Hypoxic ischemic HI injury

Introduction Hypoxic–ischemic (HI) injury to the prenatal and perinatal dihydroergotamine is a major contributor to global child mortality and morbidity (Volpe, 2001). Perinatal hypoxic–ischemic injury affects between 1 and 8 per 1000 full-term infants and nearly 60% of low birth-weight (premature) infants (Vannucci, 2000; Wagner et al., 1999). Birth asphyxia is the cause of 20 to 50% of all neonatal deaths worldwide. Approximately 25% of children who survive birth asphyxia develop permanent neurological dysfunctions including cerebral palsy, mental retardation, learning disabilities, and epilepsy (Ashwal, 1993; Vannucci, 2000; Volpe, 2001; Wagner et al., 1999). Although the exact cause of HI encephalopathy is not always identified, antecedents include prolapsed umbilical cord, uterine rupture, placental damage, maternal hypotension and acute neonatal and maternal hemorrhage. The outcome from HI injury is further influenced by a variety of factors that include the gestational age as well as the nature, severity, and duration of hypoxic–ischemic insult. Despite advances in supportive care, no effective treatment strategies for HI brain injury are available at present and only partial benefit from hypothermia for neonates with moderate hypoxic–ischemic injury has been realized (Edwards et al., 2010). Hypoxic-preconditioning (PC) is a phenomenon in which mild episodes of hypoxia induce a significant increase in resistance of neurons to subsequent damaging influences of severe hypoxia–ischemia (Dirnagl et al., 2003; Gidday, 2006; Ran et al., 2005). This initial PC stimulus triggers a cascade of endogenous adaptive mechanisms resulting in the development of tolerance. Although the molecular mechanisms of PC-induced neural hypoxic–ischemic tolerance are not completely understood, recent studies showed that PC in adult and neonatal rodents induced by brief carotid or middle cerebral artery occlusions afford neuroprotection when it precedes the lethal ischemic insult by 1–7days (Gidday et al., 1994; Kitagawa et al., 1991; Stagliano et al., 1999; Vannucci et al., 1998). We have recently demonstrated for the first time the protective efficacy of hypoxic-preconditioning against hypoxic–ischemic injury in newborn piglet model (Ara et al., 2011). Neural stem/progenitor cells (NSPs) are multipotent precursors that self-renew and retain the ability to differentiate into neurons, astrocytes and oligodendrocytes (Okano, 2002a,b). They reside throughout life in neurogenic zones such as the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (Palmer et al., 1995; Reynolds et al., 1992; Sanai et al., 2004). Recent advances in stem cell research, including selective expansion of neural stem/progenitor cells (NSPs) in vitro, identification of NSPs in the brain and detection of neurogenesis in brain, have laid the groundwork for the development of novel therapies aimed at inducing regeneration in the damaged central nervous system (CNS). Two main strategies have evolved from our recent understanding of stem cell biology. The first one consists of grafting NSPs to replace the dying cells; the second aims at recruiting endogenous stem cells or progenitors to the lesion sites (Emsley et al., 2005; Scheffler et al., 2006). There is increasing evidence to support the existence of endogenous compensatory mechanisms, which are activated in response to injury and disease (Li and Chopp, 1999; Li et al., 1997; Lindvall and McKay, 2003). Brain injury caused by cerebral ischemia, seizures, or traumatic injury (Dempsey et al., 2003; Gould et al., 1997; Gu et al., 2000; Jin et al., 2001; Liu et al., 1998; Parent et al., 1997) can stimulate neurogenesis in SVZ and dentate gyrus (DG) of hippocampus, and direct the migration of newly produced neurons towards affected regions (Arvidsson et al., 2002; Hicks et al., 2007; Jin et al., 2003; Nakatomi et al., 2002; Parent et al., 2002a,b; Sun et al., 2007). Several studies demonstrate that newborn neurons migrate toward ischemic lesions, where they might participate in brain repair and functional recovery (Jin et al., 2003; Nakatomi et al., 2002; Parent et al., 2002a; Sun et al., 2007). However, the number of newly generated neurons remains insufficient to restore normal brain function (Arvidsson et al., 2002; Bjorklund and Lindvall, 2000). To overcome this limitation, the manipulation of NSPs has developed into a key strategy for brain repair. The proliferation potential of progenitor cells can be enhanced by external stimulators, e.g. environmental enrichment (Komitova et al., 2002), caloric restriction, exercise and growth factors (Dempsey et al., 2003; Jin et al., 2002; Sun et al., 2003) and by hypoxic preconditioning (Li et al., 2010; Liu et al., 1998; Naylor et al., 2005). PC triggers an adaptive response that prepares the brain to minimize damage and promote regeneration in the event of future ischemic insult. The investigation of endogenous pathways by which the brain protects itself from ischemia represents a novel paradigm for research into cerebral hypoxia–ischemia — one that holds promise for identifying unique hypoxic–ischemic therapeutics.