brain injury concept covers a lot of heterogeneity in terms of aetiology involving multiple factors genetic hemodynamic metabolic nutritional endocrinological toxic and infectious mechanisms acting in antenatal or postnatal period. therapies to prevent brain injury and long-term neurodevelopmental impairment. 1 Introduction The most common causes of neonatal brain injury in developing countries are extreme prematurity neonatal stroke and hypoxic-ischemic encephalopathy (HIE) [1]. Extreme prematurity leads to an increased risk of death or long-term neurodevelopmental impairment including cerebral palsy (CP) [2-4] but it also contributes to half of pediatric costs for health care. The second and third trimesters represent Nobiletin the most important period for brain development with a rapid increase in size shape and complexity [5]. Hypoxia-ischemia inflammation and oxidative stress can lead to an interruption of normal brain development especially during this delicate period resulting in structural biochemical and cell-specific injury [6]. The preoligodendrocytes which emerge and mature between 24 and 32 weeks of development are particularly susceptible to injury such as intracranial hemorrhage periventricular leukomalacia and other inflammatory conditions and this damage can result in white matter injury [7 8 Oxidative stress (OS) plays a fundamental role in early injury along with other mechanisms such as excitotoxicity to the neonatal brain. OS in vivo is a degenerative process due to overproduction of free Nobiletin radicals (FRs) (reactive oxygen species and reactive nitrogen species) and propagation of their reactions. These FRs include superoxide anion (O2?) hydroxyl radical (OH) singlet oxygen (1O2) and hydrogen peroxide Nobiletin (H2O2). FRs cause damage to lipids protein and DNA initiating a cascade that results in cell death [9]. OS exists and tissue damage is possible when there are low levels of antioxidants or increased FR activity [10]. Brain cells death at any age is primarily due to hypoxia and energy depletion followed by reperfusion and FR overproduction. Excitotoxicity and nitric oxide (NO) production are responsible of secondary energy failure and delayed death. All these deleterious biological events trigger the inflammatory response with cytokine production which plays a major role in cell damage and loss. Local microglia are activated producing proinflammatory cytokines such as tumor necrosis factor- (TNF-) alpha interleukin- (IL-) 1b and IL-6 as well as glutamate FR and NO and are the main immunocompetent cells in the immature brain [11]. Newborns and particularly preterm infants are at high risk for OS and damage due to their organs’ structural and functional immaturity with the lack of antioxidant enzyme production Nobiletin the overloading Nobiletin of aerobic metabolism with rapidly growing energy demand and the presence of conditions leading to increased Nobiletin free iron levels with excessive FR production. Neonatal FLJ31599 plasma has profoundly disturbed antioxidant profiles with low levels of gluthatione peroxidase activity superoxide dismutase via enhancing perfusion of the brain if necessary [33 34 NO can react with superoxide to form peroxynitrite which can cause nitration of proteins predominantly on tyrosine residues contributing to further damage to brain tissue [35]. Selective inhibition of nNOS and iNOS with the nNOS inhibitor 7 and the iNOS inhibitor aminoguanidine have been proved to be promising as neuroprotectants in neonatal rats [36-38]. The pharmacologic inhibition of nNOS or its genetic deletion confers neuroprotection in animal models of transient cerebral ischemia [38 39 Iminobiotin inhibits both the neuronal and inducible isoforms of nitric oxide synthase. Otherwise in vivo it provides neuroprotection probably hindering apoptotic pathways. Nijboer et al. exhibited that treatment with 2-iminobiotin provided gender specific long- and short-term neuroprotection in female newborn rats with hypoxia-ischemia via inhibition of the cytochrome c-caspase 3 neuronal death pathway [40]. However only female and..