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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Clin Perinatol. Author manuscript; available in PMC 2010 December 1.
Published in final edited form as:
PMCID: PMC2786822

Neuroprotection in the Newborn Infant


Neonatal brain injury is an important cause of death and disability, with pathways of oxidant stress, inflammation, and excitotoxicity that lead to damage that progresses over a long period of time. Therapies have classically targeted individual pathways during early phases of injury, but more recent therapies such as growth factors may also enhance cell proliferation, differentiation and migration over time. More recent evidence suggests combined therapy may optimize repair, decreasing cell injury while increasing newly born cells.

Keywords: neonatal stroke, hypoxia, ischemia, neuroprotection, neurogenesis

Causes of early brain injury include stroke, birth trauma, metabolic or genetic disorders, status epilepticus, and asphyxial events. Perinatal asphyxia presents as encephalopathy, or hypoxic ischemic encephalopathy, occurring in 3 to 5 in 1000 live births [1], while stroke studies conservatively estimate an incidence of 1 in 4000 live births [2]. It is classically thought that hypoxic-ischemic (HI) injury leads to periventricular white matter damage in premature infants, while term infants develop cortical/subcortical lesions [3], but more recent evidence suggests that this distinction in injury type may not be so clear [4]. While many suffering from perinatal brain injury die during early life, the majority of survivors exhibit neurological deficits that persist, such as cerebral palsy, mental retardation or epilepsy [5]. Aside from hypothermia, no established therapies exist, and treatment and care for the sequelae of early brain injury requires significant resources. Even after maximal care, there is often little improvement in an individual's overall abilities, with long-term effects on the family, health care system, and society [6].

A search for therapies that can prevent injury progression or enhance repair of the immature brain continues, with the goal of improving long-term motor and cognitive outcomes. Because the neonatal and adult brain do not respond to insults in the same manner, secondary to differences in gene regulation during hypoxia and altered susceptibility to oxidative stress and excitotoxicity, alternate therapies must be sought [7]. Damage occurs via multiple pathways, and repair occurs over a period of days to weeks, if not months [8]. While some therapies that manipulate injury pathways show promise, not all neonates will benefit from treatment. Damage may be so severe or prolonged that repair may not be possible, or survivors may be particularly devastated [9].

The term “neuroprotection” is frequently used to describe the treatment response to brain injury, but should we think only about protecting neurons? Optimizing therapy for early brain injury requires capitalizing on multiple pathways that not only prevent cell death, but also enhance cell growth, differentiation, and long term integration into neural networks. In addition to neuronal damage, injury to non-neuronal cell types, such as oligodendrocytes and astrocytes, adversely affects development and results in long-term morbidity. By targeting the response to injury, the goal is to utilize selected pharmacotherapies to salvage cells that would otherwise die, protect cells from becoming injured or at risk for death by increasing tolerance, and also repair injured cells and enhance neurogenesis. Recent evidence suggests that therapies may be combined to enhance the protective and reparative processes, and thought must be given to the best time to administer these interventions. Clearly, because injury evolves over long periods of time with different mechanistic phases, therapies will also need to be administered over long periods of time, with different drugs aimed at these temporally evolving targets.

To maximize the efficacy of post-injury treatment, we need to identify quickly those neonates that will benefit from these therapies. A variety of clinical predictors have been used to identify those at risk for hypoxic brain injury. These include low Apgar scores, cord blood or early arterial acidosis, and seizures or the presence of encephalopathy on examination [10]. Cerebral function monitoring using bedside amplitude integrated EEG (aEEG) has provided an efficient means for identifying encephalopathy or prolonged seizure [11], but it does not replace full EEG [12]. Brain imaging with magnetic resonance imaging (MRI), including newer techniques such as spectroscopy (MRS), diffusion weighted (DWI) and diffusion tensor imaging (DTI), and volumetric analyses, provides the most accurate assessment of injury [13]. These techniques allow determination of the severity and evolution of brain injury, with specific injury patterns being associated with poor outcomes such as loss of gray/white differentiation, watershed injury, and thalamic or basal ganglia injury [14]. However, early and sequential imaging in neonates is often not possible because of scanner availability or difficulty in transporting these critically ill patients. Biomarkers for oxidative stress and inflammation, or indicators of injury to other organ systems, are currently being studied but are of equivocal value in identifying early neonatal brain injury. Given all of the available evidence, a combination of encephalopathic physical exam and seizures provides the best estimate of infants that may be at risk for brain injury [10]. This review will focus on recent developments in treating neonatal brain injury, as well as on combination therapy that will potentially enhance repair and optimize long-term outcomes.


Therapeutic hypothermia has now become standard of care for neonatal HI brain injury. Multiple animal models of perinatal brain injury demonstrate histological and functional benefit of early initiation of hypothermia [15-19] (Table 1). Brief hypothermia provides partial neuroprotection [20, 21], but prolonged moderate hypothermia to 32-34°C for 24-72 hours results in sustained improvement in behavioral performance in both newborn and adult animals [18, 19]. The only complications noted are transient effects on heart rate and blood pressure [22].

Table 1
Hypothermia Studies (discussed in text)

Studies of therapeutic hypothermia in human neonates show a reduction in mortality and long-term neurodevelopmental disability at 12-24 months of age, with the most benefit seen in moderately encephalopathic infants [9, 23-25]. Sustained protection does depend on the dose of hypothermia, with maximum benefit obtained with cooling to 33-34°C, as well as on limited delay to treatment initiation [18, 26]. Mild hypothermia to this level appears to be well tolerated without serious adverse effects if initiated within the first 6 hours of life [23, 27-29]. Recent evidence shows that there are no changes in arterial blood pressure [30], but there may be some mild changes in blood gas parameters [31]. There also appears to be an increased risk of pulmonary hypertension in cooled infants, although generally not severe [32]. In selective head cooling, treatment benefits infants with moderate, but not severe, aEEG changes, improving survival without severe neurodevelopmental deficits or an increase in complications [9]. In addition to severity of encephalopathy, larger infants appear to be more responsive to hypothermia and at more risk for injury if hyperthermic at any point [33, 34]. In a second multicenter trial, whole-body cooling to 33.5°C initiated within 6 hours and continued for 72 hours resulted in less death and severe disability at 18 to 22 months [35]. Whole-body cooling may be more effective in reducing temperature in the deep brain structures [36], and may be more feasible in certain clinical settings [37].


The response of the immature brain to milder forms of injury can help us learn about mechanisms the brain uses to protect itself from insults. Animals treated with sublethal stress are protected from subsequent insults that would otherwise be deadly [38, 39]. For example, immature rats that are exposed to hypoxia have reduced brain injury following HI that occurs 24 hours after this preconditioning stimulus, with protection that persists 1-3 weeks later [40, 41]. It is possible that injury may only be delayed, and protection may not be permanent; however, hypoxic preconditioning does provide long-lasting histological and functional protection for up to 8 weeks after neonatal rodent HI [42].

Hypoxia-inducible factor 1α (HIF-1α) activation is a key modulator of the protection against subsequent HI injury that is induced by hypoxic preconditioning [38, 43]. HIF-1α is a neuronal transcription factor that stabilizes during hypoxia by binding to HIF-1β. Following stabilization, it produces a variety of downstream targets that are neuroprotective, including insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and erythropoietin (EPO).

EPO is a 34-kDa glycoprotein that was originally identified for its role in erythropoiesis, but has since been found to have a variety of other roles. Functions include modulation of the inflammatory and immune responses [44], vasogenic and proangiogenic effects through its interaction with VEGF [45, 46], as well as effects on central nervous system (CNS) development and repair. EPO and EPO receptor are expressed by a variety of different cell types in the CNS, with changing patterns during development [47]. EPO plays a vital role in neural differentiation and neurogenesis early in development, promoting neurogenesis in vitro and in vivo [48].

Increasing evidence suggests that exogenously administered EPO has a protective effect in a variety of different models of brain injury. Post-injury treatment protocols in newborn rodents have demonstrated both short- and long-term histological and behavioral improvement [49]. A single dose of EPO given immediately after neonatal HI injury in rats significantly reduces infarct volume and improves long-term spatial memory [50]. Single- and multiple-dose treatment regimens of EPO following neonatal focal ischemic stroke in rats reduce infarct volume [51] and improve both short-term sensorimotor [52] and long-term cognitive [53] outcomes, but there may be more long-lasting behavioral benefit in female rats [54]. EPO treatment initiated 24 hours after neonatal HI also decreases brain injury [55]. In addition, EPO enhances neurogenesis and directs multipotential neural stem cells toward a neuronal cell fate [45, 48, 56]. Following transient ischemic stroke, there is a temporary precursor-cell proliferation in the rodent subventricular zone (SVZ), a source of endogenous precursor cells throughout the life of the rodent, with this precursor-cell proliferation and differentiation favoring gliogenesis [57]. EPO has been shown to enhance neurogenesis in vivo in the SVZ following stroke in the adult rat [45]. Neurogenesis has also been demonstrated following EPO treatment, with an increase in newly generated cells from precursors [45, 48, 58] and possibly also an effect on cell fate commitment in vitro [45, 48].

In humans, EPO is safely used for treatment of anemia in premature infants [59]. EPO for neuroprotection is given in much higher doses (1000-5000 U/kg/dose) than for anemia, to enable crossing of the blood-brain barrier [52, 60, 61], with unknown pharmacokinetics in humans. Recently, extremely low birthweight infants tolerated doses between 500 and 2500 U/kg/dose [62] (Table 2), and studies are ongoing.

Table 2
Human Studies of Neuroprotectants (discussed in text)

VEGF is a regulator of angiogenesis that is also involved in neuronal cell proliferation and migration [63]. The endothelial microenvironment establishes a vascular niche that promotes survival and proliferation of progenitor cells, events which are tightly coordinated with angiogenesis [64]. VEGF-A is the most important member of a family of growth factors that also includes placental growth factor (PLGF) and VEGFs B, C, and D. VEGF-A is expressed in cortical neurons during early development, switching to mature glial cells near vessels during maturation. Following exposure to hypoxia, there is increased neuronal and glial expression of VEGF-A [65], directing vascularization and stimulating proliferation of neuronal and non-neuronal cell types [66-68]. VEGF also has chemotactic effects on neurogenic zones in the brain [69], increasing migration of stem cells during anoxia [70, 71]. VEGF knockout mice have severe impairments in vascularization, neuronal migration and survival [72].

In adult ischemia models, intravenous VEGF administered 1 hour after insult increases blood-brain barrier leakage and lesion size, but late administration 48 hours after ischemia enhances angiogenesis and functional performance [73]. Both topical and intracerebroventricular injection reduced infarct volume [74, 75], and benefit has been shown in neurodegenerative and traumatic models of injury as well. VEGF-overexpressing mice also show benefit from direct neuroprotection resulting from inhibition of apoptotic pathways [63].

Other trophic factors have also shown promise, but given their role in normal neurodevelopment the effects of treatment are not known. IGF-1 is important for growth and maturation of the fetal brain as well as differentiation of oligodendrocyte precursors [76]. IGF-1 has prosurvival properties that can prevent perinatal hypoxic and excitotoxic injury [77, 78], and is also effective after intranasal administration [79]. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that also provides neuroprotection in neonatal HI [80-83]. BDNF prevents spatial learning and memory impairments after injury, but its effectiveness is limited by the stage of development [82, 83]. While protective in mice when given on postnatal day 5 (P5), BDNF has no effect at later time points and actually exacerbates excitotoxicity if given on the day of birth [82].


Neural stem cells (NSCs) are multi-potent precursors that self renew and retain the ability to differentiate into a variety of neuronal and non-neuronal cell types in the CNS. They reside in neurogenic zones throughout life, such as the SVZ and the dentate gyrus of the hippocampus in rodents, and are responsible for maintaining baseline turnover of cells as well as replacing injured cells through migration to penumbral tissue after injury. NSC transplantation has shown potential as a therapeutic strategy in adult animal models of brain injury. Implanted cells integrate into injured tissue [84], decreasing volume loss [85-87] and improving behavioral outcomes [88, 89]. In neonatal models, intraventricular implantation of NSCs after HI results in their migration to injured areas [86, 87] and differentiation into neurons, astrocytes, oligodendrocytes, and undifferentiated progenitors. These cells promote regeneration, angiogenesis and neuronal cell survival in both rodent and primate models, and non-neuronal progeny inhibit inflammation and scar formation [90, 91]. While complications of implantation have not been noted in these models, efficacy does depend on time of implantation, and the therapeutic window is not known. More recent technology enables labeling of stem cells, which can then be tracked from the site of implantation through their migratory path into the ischemic tissue [92-95], making their identification and eventual outcome in humans possible.


Oxidative stress is an important component of early injury to the neonatal brain [96], resulting from the excess formation of free radicals (FR) [reactive oxygen species (ROS) and reactive nitrogen species (RNS)] under pathological conditions. These include superoxide anion (O2·), hydroxyl radical (OH·), singlet oxygen (1O2·) and hydrogen peroxide (H2O2) [97, 98]. Antioxidant defenses such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and compounds such as vitamins A, C, E, beta carotene, glutathione and ubiquinones scavenge FRs under normal conditions. Damage occurs when there is an imbalance between their generation and uptake [97]. Following HI, there is an increase in superoxide and hydroxyl radical production and rapid depletion of antioxidant stores, which leads to cell membrane damage, excitotoxic energy depletion, cytosolic calcium accumulation, and activation of pro-apoptotic genes that cause damage to cellular components and result in cell death [99].

The neonatal brain has a high rate of oxygen consumption and low concentration of anti-oxidants, making it susceptible to damage [100, 101]. In the rat, total GPx activity increases between embryonic day 18 (E18) and postnatal day 1 (P1), but is still at lower levels than that seen in the mature brain [102]. In humans, mature oligodendrocytes carry increased antioxidant enzymes compared with the oligodendrocyte precursors present in the immature brain, which may partially explain the susceptibility of premature infants to white matter damage [103-105].

In an effort to reduce oxidative damage to the neonate, a number of strategies have been employed including ROS scavengers, lipid peroxidation inhibitors, FR reducers, and nitric oxide synthase inhibitors. Nitric oxide synthase (NOS) catalyzes the synthesis of nitric oxide (NO) from the conversion of arginine to citrulline [106]. NO plays an important role in pulmonary, systemic, and cerebral vasodilation, and is constitutively produced in response to increased intracellular calcium by endothelial nitric oxide synthase (eNOS) in endothelial cells and by neuronal nitric oxide synthase (nNOS) in astrocytes and neurons. An inducible isoform of nitric oxide synthase (iNOS) also produces NO in response to cellular stress, which initiates neuronal damage when converted to secondary reactive nitrogen species that facilitate nitration and nitrosylation reactions [107]. Early endothelial NO is protective by maintaining blood flow, but early neuronal NO and late inducible NO promote cell death [108]. Brain iNOS is induced in multiple cell types during upregulation of the pro-inflammatory pathway after brain injury [109], modifying binding to NMDA receptors and enhancing excitotoxicity [110].

Selective inhibition of nNOS or iNOS has shown potential as a neuroprotective strategy [111]. Regions expressing nNOS correspond to those that are susceptible to excitoxicity, expressing NMDA receptors in vivo and in vitro [112-114]. Destruction of neurons containing nNOS or targeted disruption of the nNOS gene protects animals from HI injury [115] [113], but nonspecific blockade of nNOS and eNOS is not protective [116]. There have been few studies in human newborns examining cerebral NO production. Cerebrospinal fluid (CSF) NO levels increase with severity of HI encephalopathy at 24 to 72 hours after asphyxia [117], with increased NO and nitrotyrosine levels in the spinal cord as well [118]. Initial results in premature infants treated with inhaled NO for prevention of bronchopulmonary dysplasia show reductions in ultrasound-diagnosed brain injury and improvements in neurodevelopmental outcomes at 2 years of age, but long-term results are still pending [119, 120].

Several other antioxidant strategies that either block FR production or increase antioxidant defenses are being studied. Melatonin is an indoleamine that is formed in higher quantities in adults and functions as a direct scavenger of ROS and NO. It has been found to provide long-lasting neuroprotection in experimental HI and focal cerebral ischemic injury [121, 122], and human neonates treated with melatonin were also found to have decreased pro-inflammatory cytokines [123, 124]. Allopurinol has mixed effects that have shown promise in animal and human studies. Xanthine oxidase-derived superoxide and H2O2 react with NO to form damaging RNS. Allopurinol reduces FR production by inhibiting xanthine oxidase while also scavenging hydroxyl radicals. High-dose allopurinol given 15 minutes after HI in P7 rats decreases acute edema and long-term infarct volume [125]. Short-term benefits have also been seen in neonates undergoing cardiac surgery for hypoplastic left heart syndrome [126]. Early allopurinol in asphyxiated infants improved short-term neurodevelopmental outcomes and decreased serum NO levels after administration; however, there may be only a brief window for benefit, as no improvement in long-term outcomes was seen with later treatment after birth asphyxia [127]. Deferoxamine (DFO) is an iron chelator that decreases FR production by binding with iron and decreasing the production of OH· that occurs via the Fenton reaction [128, 129], while also stabilizing HIF-1α to produce its downstream products VEGF and EPO [128]. DFO is protective during exposure to H2O2 or excitotoxicity in vitro [130], and in animal models of HI and transient ischemic stroke in vivo [128, 131, 132]. N-acetylcysteine (NAC) is a glutathione precursor and FR scavenger that attenuates lipopolysaccharide-induced white matter injury in newborn rats [133, 134], but results for other antioxidant compounds, such as vitamin E, have been inconclusive [135].


Glutamate plays an important role in progenitor cell proliferation, differentiation, migration and survival in the developing brain. Excitotoxicity refers to excessive glutamatergic activation that leads to cell injury and death [136]. Glutamate accumulates in the brain after HI [137] from a variety of causes, including vesicular release [138] and reversal of glutamate transporters [139, 140]. Glutamatergic receptors include N-methyl-D-aspartate (NMDA), alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate. NMDA receptor activation, while important for synaptic plasticity [141], can increase intracellulular calcium and pro-apoptotic pathways via caspase-3 activation if overactivated [142, 143]. Excitotoxicity has long been known to play a part in the progression of HI brain injury, and differences in receptor expression contribute to the vulnerability of the developing brain [144]. NMDA, as well as AMPA and kainate, receptors on oligodendrocyte precursors play a large part in their susceptibility to damage in premature HI-induced white matter injury [145-147].

There has long been a search for agents that decrease brain injury by decreasing excitotoxicity. Dizocilipine (MK801) is a noncompetitive NMDA receptor antagonist that has been studied in humans, but is poorly tolerated and has also been shown to increase apoptosis and decrease neuronal migration in animal models [148]. Memantine is a low affinity noncompetitive NMDA receptor antagonist that is well tolerated in adults for Alzheimer's-type dementia [149]. Post-HI treatment with memantine attenuates acute white matter injury in P6 rats, resulting in long-term histological improvement in vivo and restoring neuronal migration in vitro [150-152]. Another method to decrease excitotoxicity is the use of topiramate, an AMPA-kainate receptor antagonist that is an FDA-approved anti-epileptic for patients greater than 2 years of age. It has been shown to protect newborn rodents from excitotoxic brain lesions [153], reducing brain damage and cognitive impairment when administered within two hours of the insult [154]. An IV preparation of topiramate does not yet exist for human use, but this treatment shows potential as a therapy for early newborn seizure and injury. Cannabinoids have also shown promise as a treatment for neurodegenerative disorders [155] and in adult models of ischemia [156] or trauma [157]. They are involved in control of synaptic transmission, and their receptors (CB1 and CB2) are expressed on neurons and glia [158, 159]. In the immature brain, cannabinoids have effects on excitotoxic lesions [160], and the agonist WIN 55,212-2 reduces short-term brain injury when administered after neonatal HI [161].

Magnesium sulfate has shown some benefit in preventing white matter damage in animal models [162-164], and one possible mechanism of its neuroprotection is the blockade of NMDA receptors [165]. In a multicenter clinical trial of mothers treated with magnesium who were at risk for preterm delivery, no perinatal side effects were seen and there was some benefit in the neurodevelopment of survivors [166]. However, magnesium administered to asphyxiated term neonates did not result in improvements in aEEG patterns, and when given in larger doses was associated with profound hypotension [167, 168].


Maternal infection is a known risk factor for white matter damage and poor outcomes, such as cerebral palsy [169-171]. The inflammatory response and cytokine production that accompanies infection may play a large role in cell damage and loss [172]. Local microglia are activated early and produce pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, as well as glutamate, FRs, and NO. Systemic administration of these cytokines increases excitotoxic lesions [173], while therapies that block microglial activation and cytokine release protect the brain from excitotoxic damage [174].

Minocycline is a tetracycline derivative that crosses the blood-brain barrier and has anti-inflammatory effects, including decreasing microglial activation and caspase-3 expression [175, 176], lipid peroxidation [177], and other pro-inflammatory activity [178] while increasing anti-apoptotic gene expression [179, 180]. Minocycline has shown promise in a number of animal models of neurodegenerative or ischemic disease [175, 181-185]. In the neonatal brain, minocycline appears to decrease tissue damage and caspase-3 activation in rodents when given immediately before or after injury, but results are inconsistent [186-188]. Low- and high-dose regimens were effective in reducing short-term HI-induced inflammation, protecting developing oligodendrocytes [188] and myelin content in neonatal rats [189], but this effect was only transient in another study of neonatal rodent stroke [187]. Delayed therapy was found to decrease TNF-α and matrix metalloproteinase MMP-12, but efficacy was lost when treatment was extended for a week after stroke [190]. These effects also appear to be species dependent, with an increase in injury in developing C57B1/6 mice [191].


Apoptosis is a critical component of normal brain development. While necrosis plays a major role in early neuronal death in both the immature and mature brain following injury [192], a spectrum of cell death that includes apoptosis occurs within the first 24 hours following neonatal HI [193], and may result in heterogeneous responses to anti-apoptotic therapies [194]. It is also probable that apoptosis and cleavage and activation of caspase-3 are responsible for more of the cell death that occurs in delayed phases of injury and neurodegeneration [195].

Specific and non-specific inhibition of caspases or cysteine proteases, which are highly activated after HI, has been attempted with some success [196-199]. For example, calpain or caspase-3 inhibitors such as MDL 28710 and M826 protect neonatal rats after HI [197, 200]. Pretreatment with the hormone 17β-estradiol is neuroprotective in immature rats, and appears to work through both anti-apoptotic and FR scavenging pathways [201]. In addition, the nuclear enzyme poly (ADP-ribose) polymerase (PARP) is activated during stress and enables DNA repair; however, the PARP-1 isoform also contributes to ischemic neuronal injury by depleting energy stores and activating microglia, leading to cell death. PARP-1 is more abundant in the immature brain, and its blockade protects against excitotoxicity and ischemic injury [202]. The PARP-1 inhibitor 3-aminobenzamide reduces injury after focal ischemia in P7 rats [203], but PARP-1 blockade appears to protect males preferentially [202].


Single therapy that attacks any of the aforementioned injury pathways often results in only mild improvement. For example, therapeutics targeting apoptosis may prevent delayed cell death, but would not effect earlier necrotic and excitotoxic injury. Hypothermia has become the standard of care in many institutions since showing benefit in moderately encephalopathic newborns; however, it does not completely protect or repair an injured brain, and benefits may not necessarily be long lasting [204, 205], so the search for adjuvant therapies continues. Combinatorial therapy may provide more long-lasting neuroprotection, salvaging the brain from severe injury and deficits while also enhancing repair and regeneration, hopefully providing additive, if not synergistic, protection.

Xenon is approved for use as a general anesthetic in Europe and has shown promise as a protective agent. It is an NMDA antagonist, preventing progression of excitotoxic damage. It appears to be superior to other NMDA antagonists, possibly through inhibition of AMPA and kainate receptors, reduction of neurotransmitter release, or effects on other ion channels [206-208]. Combination xenon and hypothermia initiated 4 hours after neonatal HI provided synergistic histological and functional protection when evaluated at 30 days after injury [209]. Hypothermia does reduce glutamate and glycine release [210], and NMDA receptor antagonism may explain these effects. More recently, an additive effect was shown after HI in P7 rats that were cooled to 32°C and received 50% xenon, with improvement in long-term histology and functional performance that exceeded the individual benefit of either [211]. More extensive studies on xenon use in human neonates are necessary.

N-acetylcysteine (NAC) is a medication approved for neonates that is a scavenger of oxygen radicals and restores intracellular glutathione levels, attenuating reperfusion injury and decreasing inflammation and NO production in adult models of stroke [212, 213]. Adding NAC therapy to systemic hypothermia reduced brain volume loss at both 2 and 4 weeks after neonatal rodent HI, with increased myelin expression and improved reflexes [214]. Inhibition of inflammation with MK-801 has also been effective when combined with hypothermia in neonatal rats post HI injury [215]. In P7 rats who underwent HI followed by early topiramate and delayed hypothermia, improved short-term histology and function was seen [216]. The inhibition of inflammation may provide a window for protection if hypothermia is delayed, which is possible given difficulty in initiation of cooling if infants are born at an outside hospital or transport is delayed.


Most studies have focused on singular mechanisms of injury, such as oxidative stress, inflammation, and excitotoxicity. More recent evidence suggests that injury occurs over long periods of time and that therapies may need to be administered over much longer periods than have been previously entertained. While hypothermia and single pharmacotherapies show promise, combined therapy may be necessary to increase the therapeutic time window for protection and repair, making recovery possible.


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1. Wu YW, Backstrand KH, Zhao S, Fullerton HJ, Johnston SC. Declining diagnosis of birth asphyxia in California: 1991-2000. Pediatrics. 2004 Dec;114(6):1584–1590. [PubMed]
2. Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurol. 2004 Mar;3(3):150–158. [PubMed]
3. Gressens P, Luton D. Fetal MRI: obstetrical and neurological perspectives. Pediatr Radiol. 2004 Sep;34(9):682–684. [PubMed]
4. Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007 Nov 8;357(19):1928–1938. [PubMed]
5. Dilenge ME, Majnemer A, Shevell MI. Long-term developmental outcome of asphyxiated term neonates. J Child Neurol. 2001 Nov;16(11):781–792. [PubMed]
6. Ferriero DM. Neonatal brain injury. N Engl J Med. 2004 Nov 4;351(19):1985–1995. [PubMed]
7. McQuillen PS, Ferriero DM. Selective vulnerability in the developing central nervous system. Pediatr Neurol. 2004 Apr;30(4):227–235. [PubMed]
8. Geddes R, Vannucci RC, Vannucci SJ. Delayed cerebral atrophy following moderate hypoxia-ischemia in the immature rat. Dev Neurosci. 2001;23(3):180–185. [PubMed]
9. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663–670. [PubMed]
10. Miller SP, Latal B, Clark H, et al. Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy. Am J Obstet Gynecol. 2004 Jan;190(1):93–99. [PubMed]
11. Hellstrom-Westas L, Rosen I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med. 2006 Dec;11(6):503–511. [PubMed]
12. Shellhaas RA, Soaita AI, Clancy RR. Sensitivity of amplitude-integrated electroencephalography for neonatal seizure detection. Pediatrics. 2007 Oct;120(4):770–777. [PubMed]
13. Chau V, Clement JF, Robitaille Y, D'Anjou G, Vanasse M. Congenital axonal neuropathy and encephalopathy. Pediatr Neurol. 2008 Apr;38(4):261–266. [PubMed]
14. Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr. 2005 Apr;146(4):453–460. [PubMed]
15. Laptook AR, Corbett RJ, Sterett R, Burns DK, Tollefsbol G, Garcia D. Modest hypothermia provides partial neuroprotection for ischemic neonatal brain. Pediatr Res. 1994 Apr;35(4 Pt 1):436–442. [PubMed]
16. Laptook AR, Corbett RJ, Sterett R, Burns DK, Garcia D, Tollefsbol G. Modest hypothermia provides partial neuroprotection when used for immediate resuscitation after brain ischemia. Pediatr Res. 1997 Jul;42(1):17–23. [PubMed]
17. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res. 1995 May;37(5):667–670. [PubMed]
18. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997 Jan 15;99(2):248–256. [PMC free article] [PubMed]
19. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics. 1998 Nov;102(5):1098–1106. [PubMed]
20. Towfighi J, Housman C, Heitjan DF, Vannucci RC, Yager JY. The effect of focal cerebral cooling on perinatal hypoxic-ischemic brain damage. Acta Neuropathol. 1994;87(6):598–604. [PubMed]
21. Laptook AR, Corbett RJ. The effects of temperature on hypoxic-ischemic brain injury. Clin Perinatol. 2002 Dec;29(4):623–649. vi. [PubMed]
22. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics. 2000 Jul;106(1 Pt 1):92–99. [PubMed]
23. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics. 1998 Oct;102(4 Pt 1):885–892. [PubMed]
24. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005 Jan;32(1):11–17. [PubMed]
25. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574–1584. [PubMed]
26. Bona E, Hagberg H, Loberg EM, Bagenholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res. 1998 Jun;43(6):738–745. [PubMed]
27. Azzopardi D, Robertson NJ, Cowan FM, Rutherford MA, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics. 2000 Oct;106(4):684–694. [PubMed]
28. Thoresen M. Cooling the newborn after asphyxia - physiological and experimental background and its clinical use. Semin Neonatol. 2000 Feb;5(1):61–73. [PubMed]
29. Shankaran S, Laptook A, Wright LL, et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002 Aug;110(2 Pt 1):377–385. [PubMed]
30. Battin MR, Thoresen M, Robinson E, Polin RA, Edwards AD, Gunn AJ. Does head cooling with mild systemic hypothermia affect requirement for blood pressure support? Pediatrics. 2009 Mar;123(3):1031–1036. [PubMed]
31. Groenendaal F, De Vooght KM, van Bel F. Blood gas values during hypothermia in asphyxiated term neonates. Pediatrics. 2009 Jan;123(1):170–172. [PubMed]
32. Sarkar S, Barks JD, Bhagat I, Dechert R, Donn SM. Pulmonary dysfunction and therapeutic hypothermia in asphyxiated newborns: whole body versus selective head cooling. Am J Perinatol. 2009 Apr;26(4):265–270. [PubMed]
33. Wyatt JS, Gluckman PD, Liu PY, et al. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics. 2007 May;119(5):912–921. [PubMed]
34. Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. 2008 Sep;122(3):491–499. [PMC free article] [PubMed]
35. Shankaran S, Pappas A, Laptook AR, et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008 Oct;122(4):e791–798. [PMC free article] [PubMed]
36. Van Leeuwen GM, Hand JW, Lagendijk JJ, Azzopardi DV, Edwards AD. Numerical modeling of temperature distributions within the neonatal head. Pediatr Res. 2000 Sep;48(3):351–356. [PubMed]
37. Robertson NJ, Nakakeeto M, Hagmann C, et al. Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial. Lancet. 2008 Sep 6;372(9641):801–803. [PubMed]
38. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol. 2000 Sep;48(3):285–296. [PubMed]
39. Sheldon RA, Aminoff A, Lee CL, Christen S, Ferriero DM. Hypoxic preconditioning reverses protection after neonatal hypoxia-ischemia in glutathione peroxidase transgenic murine brain. Pediatr Res. 2007 Jun;61(6):666–670. [PubMed]
40. Gidday JM, Fitzgibbons JC, Shah AR, Park TS. Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci Lett. 1994 Feb 28;168(12):221–224. [PubMed]
41. Vannucci RC, Towfighi J, Vannucci SJ. Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J Neurochem. 1998 Sep;71(3):1215–1220. [PubMed]
42. Gustavsson M, Anderson MF, Mallard C, Hagberg H. Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats. Pediatr Res. 2005 Feb;57(2):305–309. [PubMed]
43. Ran R, Xu H, Lu A, Bernaudin M, Sharp FR. Hypoxia preconditioning in the brain. Dev Neurosci. 2005 Mar-Aug;27(24):87–92. [PubMed]
44. Villa P, Bigini P, Mennini T, et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med. 2003 Sep 15;198(6):971–975. [PMC free article] [PubMed]
45. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004 Jul;35(7):1732–1737. [PubMed]
46. Chong ZZ, Kang JQ, Maiese K. Angiogenesis and plasticity: role of erythropoietin in vascular systems. J Hematother Stem Cell Res. 2002 Dec;11(6):863–871. [PubMed]
47. Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol. 1999 Mar-Apr;2(2):148–158. [PubMed]
48. Shingo T, Sorokan ST, Shimazaki T, Weiss S. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci. 2001 Dec 15;21(24):9733–9743. [PubMed]
49. Sola A, Wen TC, Hamrick SE, Ferriero DM. Potential for protection and repair following injury to the developing brain: a role for erythropoietin? Pediatr Res. 2005 May;57(5 Pt 2):110R–117R. [PubMed]
50. Kumral A, Uysal N, Tugyan K, et al. Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats. Behav Brain Res. 2004 Aug 12;153(1):77–86. [PubMed]
51. Sola A, Rogido M, Lee BH, Genetta T, Wen TC. Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. Pediatr Res. 2005 Apr;57(4):481–487. [PubMed]
52. Chang YS, Mu D, Wendland M, et al. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res. 2005 Jul;58(1):106–111. [PubMed]
53. Gonzalez FF, Abel R, Almli CR, Mu D, Wendland M, Ferriero DM. Erythropoietin Sustains Cognitive Function and Brain Volume after Neonatal Stroke. Dev Neurosci. in press. [PMC free article] [PubMed]
54. Wen TC, Rogido M, Peng H, Genetta T, Moore J, Sola A. Gender differences in long-term beneficial effects of erythropoietin given after neonatal stroke in postnatal day-7 rats. Neuroscience. 2006;139(3):803–811. [PubMed]
55. Sun Y, Calvert JW, Zhang JH. Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration. Stroke. 2005 Aug;36(8):1672–1678. [PubMed]
56. Gonzalez FF, McQuillen P, Mu D, et al. Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci. 2007;29(45):321–330. [PubMed]
57. Plane JM, Liu R, Wang TW, Silverstein FS, Parent JM. Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis. 2004 Aug;16(3):585–595. [PubMed]
58. Lu D, Mahmood A, Qu C, Goussev A, Schallert T, Chopp M. Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma. 2005 Sep;22(9):1011–1017. [PubMed]
59. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2006;3:CD004868. [PubMed]
60. Demers EJ, McPherson RJ, Juul SE. Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia. Pediatr Res. 2005 Aug;58(2):297–301. [PubMed]
61. McPherson RJ, Juul SE. High-dose erythropoietin inhibits apoptosis and stimulates proliferation in neonatal rat intestine. Growth Horm IGF Res. 2007 Oct;17(5):424–430. [PubMed]
62. Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Maycock DE. A Phase I/II Trial of High Dose Erythropoietin in Extremely Low Birth Weight Infants: Pharmacokinetics and Safety. Pediatrics. 2008 Aug;122(2):504–510. [PubMed]
63. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals. 2005;14(5):207–221. [PubMed]
64. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000 Oct 2;425(4):479–494. [PubMed]
65. Krum JM, Rosenstein JM. VEGF mRNA and its receptor flt-1 are expressed in reactive astrocytes following neural grafting and tumor cell implantation in the adult CNS. Exp Neurol. 1998 Nov;154(1):57–65. [PubMed]
66. Forstreuter F, Lucius R, Mentlein R. Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells. J Neuroimmunol. 2002 Nov;132(12):93–98. [PubMed]
67. Mu D, Jiang X, Sheldon RA, et al. Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiol Dis. 2003 Dec;14(3):524–534. [PubMed]
68. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11946–11950. [PubMed]
69. Yang X, Cepko CL. Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J Neurosci. 1996 Oct 1;16(19):6089–6099. [PubMed]
70. Maurer MH, Tripps WK, Feldmann RE, Jr., Kuschinsky W. Expression of vascular endothelial growth factor and its receptors in rat neural stem cells. Neurosci Lett. 2003 Jul 3;344(3):165–168. [PubMed]
71. Bagnard D, Vaillant C, Khuth ST, et al. Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci. 2001 May 15;21(10):3332–3341. [PubMed]
72. Raab S, Beck H, Gaumann A, et al. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost. 2004 Mar;91(3):595–605. [PubMed]
73. Zhang ZG, Zhang L, Jiang Q, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000 Oct;106(7):829–838. [PMC free article] [PubMed]
74. Hayashi T, Abe K, Itoyama Y. Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab. 1998 Aug;18(8):887–895. [PubMed]
75. Harrigan MR, Ennis SR, Sullivan SE, Keep RF. Effects of intraventricular infusion of vascular endothelial growth factor on cerebral blood flow, edema, and infarct volume. Acta Neurochir (Wien) 2003 Jan;145(1):49–53. [PubMed]
76. D'Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G. The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol. 1996 Dec;13(3):227–255. [PubMed]
77. Johnston BM, Mallard EC, Williams CE, Gluckman PD. Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs. J Clin Invest. 1996 Jan 15;97(2):300–308. [PMC free article] [PubMed]
78. Pang Y, Zheng B, Fan LW, Rhodes PG, Cai Z. IGF-1 protects oligodendrocyte progenitors against TNFalpha-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway. Glia. 2007 Aug 15;55(11):1099–1107. [PubMed]
79. Lin S, Fan LW, Rhodes PG, Cai Z. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol. 2009 Mar 28; [PMC free article] [PubMed]
80. Cheng Y, Gidday JM, Yan Q, Shah AR, Holtzman DM. Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic-ischemic brain injury. Ann Neurol. 1997 Apr;41(4):521–529. [PubMed]
81. Holtzman DM, Sheldon RA, Jaffe W, Cheng Y, Ferriero DM. Nerve growth factor protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol. 1996 Jan;39(1):114–122. [PubMed]
82. Husson I, Rangon CM, Lelievre V, et al. BDNF-induced white matter neuroprotection and stage-dependent neuronal survival following a neonatal excitotoxic challenge. Cereb Cortex. 2005 Mar;15(3):250–261. [PubMed]
83. Cheng ET, Utley DS, Ho PR, et al. Functional recovery of transected nerves treated with systemic BDNF and CNTF. Microsurgery. 1998;18(1):35–41. [PubMed]
84. Park KI, Teng YD, Snyder EY. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol. 2002 Nov;20(11):1111–1117. [PubMed]
85. Hoehn M, Kustermann E, Blunk J, et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16267–16272. [PubMed]
86. Park KI, Himes BT, Stieg PE, Tessler A, Fischer I, Snyder EY. Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: Evidence from engraftment of Neurotrophin-3-expressing stem cells in hypoxic-ischemic brain injury. Exp Neurol. 2006 May;199(1):179–190. [PubMed]
87. Park KI, Hack MA, Ourednik J, et al. Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: evidence from the effect of hypoxia-ischemia in the CNS on clonal “reporter” neural stem cells. Exp Neurol. 2006 May;199(1):156–178. [PubMed]
88. Capone C, Frigerio S, Fumagalli S, et al. Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment. PLoS ONE. 2007;2(4):e373. [PMC free article] [PubMed]
89. Hicks AU, Hewlett K, Windle V, et al. Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke. Neuroscience. 2007 Apr 25;146(1):31–40. [PubMed]
90. Imitola J, Raddassi K, Park KI, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18117–18122. [PubMed]
91. Mueller FJ, Serobyan N, Schraufstatter IU, et al. Adhesive interactions between human neural stem cells and inflamed human vascular endothelium are mediated by integrins. Stem Cells. 2006 Nov;24(11):2367–2372. [PMC free article] [PubMed]
92. Modo M, Mellodew K, Cash D, et al. Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study. Neuroimage. 2004 Jan;21(1):311–317. [PubMed]
93. Guzman R, Uchida N, Bliss TM, et al. Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10211–10216. [PubMed]
94. Rice HE, Hsu EW, Sheng H, et al. Superparamagnetic iron oxide labeling and transplantation of adipose-derived stem cells in middle cerebral artery occlusion-injured mice. AJR Am J Roentgenol. 2007 Apr;188(4):1101–1108. [PubMed]
95. Obenaus A, Robbins M, Blanco G, et al. Multi-modal magnetic resonance imaging alterations in two rat models of mild neurotrauma. J Neurotrauma. 2007 Jul;24(7):1147–1160. [PubMed]
96. Ferriero DM. Oxidant mechanisms in neonatal hypoxia-ischemia. Dev Neurosci. 2001;23(3):198–202. [PubMed]
97. Fridovich I. Superoxide anion radical (O2-.), superoxide dismutases, and related matters. J Biol Chem. 1997 Jul 25;272(30):18515–18517. [PubMed]
98. Halliwell B. Antioxidant defence mechanisms: from the beginning to the end (of the beginning) Free Radic Res. 1999 Oct;31(4):261–272. [PubMed]
99. Taylor DL, Edwards AD, Mehmet H. Oxidative metabolism, apoptosis and perinatal brain injury. Brain Pathol. 1999 Jan;9(1):93–117. [PubMed]
100. Buonocore G, Perrone S, Bracci R. Free radicals and brain damage in the newborn. Biol Neonate. 2001;79(34):180–186. [PubMed]
101. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006 Jun;97(6):1634–1658. [PubMed]
102. Khan JY, Black SM. Developmental changes in murine brain antioxidant enzymes. Pediatr Res. 2003 Jul;54(1):77–82. [PubMed]
103. Baud O, Li J, Zhang Y, Neve RL, Volpe JJ, Rosenberg PA. Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. Eur J Neurosci. 2004 Oct;20(7):1713–1726. [PubMed]
104. Volpe JJ. Brain injury in the premature infant. Neuropathology, clinical aspects, pathogenesis, and prevention. Clin Perinatol. 1997 Sep;24(3):567–587. [PubMed]
105. Haynes RL, Baud O, Li J, Kinney HC, Volpe JJ, Folkerth DR. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol. 2005 Jul;15(3):225–233. [PubMed]
106. Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci. 1999 Jul;55(89):1015–1028. [PubMed]
107. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996 Nov;271(5 Pt 1):C1424–1437. [PubMed]
108. Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci. 1997 Dec 1;17(23):9157–9164. [PubMed]
109. Higuchi Y, Hattori H, Kume T, Tsuji M, Akaike A, Furusho K. Increase in nitric oxide in the hypoxic-ischemic neonatal rat brain and suppression by 7-nitroindazole and aminoguanidine. Eur J Pharmacol. 1998 Jan 19;342(1):47–49. [PubMed]
110. Ishida A, Trescher WH, Lange MS, Johnston MV. Prolonged suppression of brain nitric oxide synthase activity by 7-nitroindazole protects against cerebral hypoxic-ischemic injury in neonatal rat. Brain Dev. 2001 Aug;23(5):349–354. [PubMed]
111. van den Tweel ER, van Bel F, Kavelaars A, et al. Long-term neuroprotection with 2-iminobiotin, an inhibitor of neuronal and inducible nitric oxide synthase, after cerebral hypoxia-ischemia in neonatal rats. J Cereb Blood Flow Metab. 2005 Jan;25(1):67–74. [PubMed]
112. Black SM, Bedolli MA, Martinez S, Bristow JD, Ferriero DM, Soifer SJ. Expression of neuronal nitric oxide synthase corresponds to regions of selective vulnerability to hypoxia-ischaemia in the developing rat brain. Neurobiol Dis. 1995 Jun;2(3):145–155. [PubMed]
113. Ferriero DM, Holtzman DM, Black SM, Sheldon RA. Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. Neurobiol Dis. 1996 Feb;3(1):64–71. [PubMed]
114. Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH. Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J Neurosci. 1993 Jun;13(6):2651–2661. [PubMed]
115. Ferriero DM, Sheldon RA, Black SM, Chuai J. Selective destruction of nitric oxide synthase neurons with quisqualate reduces damage after hypoxia-ischemia in the neonatal rat. Pediatr Res. 1995 Dec;38(6):912–918. [PubMed]
116. Marks KA, Mallard CE, Roberts I, Williams CE, Gluckman PD, Edwards AD. Nitric oxide synthase inhibition attenuates delayed vasodilation and increases injury after cerebral ischemia in fetal sheep. Pediatr Res. 1996 Aug;40(2):185–191. [PubMed]
117. Ergenekon E, Gucuyener K, Erbas D, Suheyl Ezgu F, Atalay Y. Cerebrospinal fluid and serum nitric oxide levels in asphyxiated newborns. Biol Neonate. 1999 Oct;76(4):200–206. [PubMed]
118. Groenendaal F, Vles J, Lammers H, De Vente J, Smit D, Nikkels PG. Nitrotyrosine in human neonatal spinal cord after perinatal asphyxia. Neonatology. 2008;93(1):1–6. [PubMed]
119. Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003 Nov 27;349(22):2099–2107. [PubMed]
120. Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006 Jul 27;355(4):343–353. [PubMed]
121. Carloni S, Perrone S, Buonocore G, Longini M, Proietti F, Balduini W. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res. 2008 Mar;44(2):157–164. [PubMed]
122. Koh PO. Melatonin attenuates the focal cerebral ischemic injury by inhibiting the dissociation of pBad from 14-3-3. J Pineal Res. 2008 Jan;44(1):101–106. [PubMed]
123. Gitto E, Reiter RJ, Cordaro SP, et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol. 2004 May;21(4):209–216. [PubMed]
124. Gitto E, Reiter RJ, Sabatino G, et al. Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: improvement with melatonin treatment. J Pineal Res. 2005 Oct;39(3):287–293. [PubMed]
125. Palmer C, Towfighi J, Roberts RL, Heitjan DF. Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res. 1993 Apr;33(4 Pt 1):405–411. [PubMed]
126. Clancy RR, McGaurn SA, Goin JE, et al. Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics. 2001 Jul;108(1):61–70. [PubMed]
127. Benders MJ, Bos AF, Rademaker CM, et al. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006 May;91(3):F163–165. [PMC free article] [PubMed]
128. Mu D, Chang YS, Vexler ZS, Ferriero DM. Hypoxia-inducible factor 1alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke. Exp Neurol. 2005 Oct;195(2):407–415. [PubMed]
129. Hamrick SE, McQuillen PS, Jiang X, Mu D, Madan A, Ferriero DM. A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection. Neurosci Lett. 2005 May 6;379(2):96–100. [PubMed]
130. Almli LM, Hamrick SE, Koshy AA, Tauber MG, Ferriero DM. Multiple pathways of neuroprotection against oxidative stress and excitotoxic injury in immature primary hippocampal neurons. Brain Res Dev Brain Res. 2001 Dec 31;132(2):121–129. [PubMed]
131. Palmer C, Roberts RL, Bero C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke. 1994 May;25(5):1039–1045. [PubMed]
132. Sarco DP, Becker J, Palmer C, Sheldon RA, Ferriero DM. The neuroprotective effect of deferoxamine in the hypoxic-ischemic immature mouse brain. Neurosci Lett. 2000 Mar 17;282(12):113–116. [PubMed]
133. Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593–597. [PubMed]
134. Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK. N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res. 2004 Nov 1;78(3):347–361. [PubMed]
135. Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2003;(4):CD003665. [PubMed]
136. Olney JW. Excitotoxicity, apoptosis and neuropsychiatric disorders. Curr Opin Pharmacol. 2003 Feb;3(1):101–109. [PubMed]
137. Gucuyener K, Atalay Y, Aral YZ, Hasanoglu A, Turkyilmaz C, Biberoglu G. Excitatory amino acids and taurine levels in cerebrospinal fluid of hypoxic ischemic encephalopathy in newborn. Clin Neurol Neurosurg. 1999 Sep;101(3):171–174. [PubMed]
138. Kukley M, Capetillo-Zarate E, Dietrich D. Vesicular glutamate release from axons in white matter. Nat Neurosci. 2007 Mar;10(3):311–320. [PubMed]
139. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature. 2000 Jan 20;403(6767):316–321. [PubMed]
140. Fern R, Moller T. Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J Neurosci. 2000 Jan 1;20(1):34–42. [PubMed]
141. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol. 2001 Jun;11(3):327–335. [PubMed]
142. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol. 2004 Aug;207(Pt 18):3149–3154. [PubMed]
143. MacDonald JF, Jackson MF, Beazely MA. Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Crit Rev Neurobiol. 2006;18(12):71–84. [PubMed]
144. Deng W, Wang H, Rosenberg PA, Volpe JJ, Jensen FE. Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7751–7756. [PubMed]
145. Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005 Dec 22;438(7071):1167–1171. [PubMed]
146. Kinney HC, Back SA. Human oligodendroglial development: relationship to periventricular leukomalacia. Semin Pediatr Neurol. 1998 Sep;5(3):180–189. [PubMed]
147. Karadottir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005 Dec 22;438(7071):1162–1166. [PMC free article] [PubMed]
148. Ikonomidou C, Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 2002 Oct;1(6):383–386. [PubMed]
149. Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006 Jun;97(6):1611–1626. [PubMed]
150. Chen HS, Wang YF, Rayudu PV, et al. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience. 1998 Oct;86(4):1121–1132. [PubMed]
151. Manning S, Talos D, Zhou C, et al. NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia. Journal of Neuroscience. in press. [PMC free article] [PubMed]
152. Volbracht C, van Beek J, Zhu C, Blomgren K, Leist M. Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity. Eur J Neurosci. 2006 May;23(10):2611–2622. [PubMed]
153. Sfaello I, Baud O, Arzimanoglou A, Gressens P. Topiramate prevents excitotoxic damage in the newborn rodent brain. Neurobiol Dis. 2005 Dec;20(3):837–848. [PubMed]
154. Noh MR, Kim SK, Sun W, et al. Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats. Exp Neurol. 2006 Oct;201(2):470–478. [PubMed]
155. Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005 May;5(5):400–411. [PubMed]
156. Nagayama T, Sinor AD, Simon RP, et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999 Apr 15;19(8):2987–2995. [PubMed]
157. Panikashvili D, Shein NA, Mechoulam R, et al. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of pro-inflammatory cytokines. Neurobiol Dis. 2006 May;22(2):257–264. [PubMed]
158. Benito C, Romero JP, Tolon RM, et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007 Feb 28;27(9):2396–2402. [PubMed]
159. Onaivi ES, Ishiguro H, Gong JP, et al. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS ONE. 2008;3(2):e1640. [PMC free article] [PubMed]
160. van der Stelt M, Veldhuis WB, van Haaften GW, et al. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci. 2001 Nov 15;21(22):8765–8771. [PubMed]
161. Fernandez-Lopez D, Pazos MR, Tolon RM, et al. The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats. Pediatr Res. 2007 Sep;62(3):255–260. [PubMed]
162. Turkyilmaz C, Turkyilmaz Z, Atalay Y, Soylemezoglu F, Celasun B. Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia-ischemia. Brain Res. 2002 Nov 15;955(12):133–137. [PubMed]
163. Marret S, Gressens P, Gadisseux JF, Evrard P. Prevention by magnesium of excitotoxic neuronal death in the developing brain: an animal model for clinical intervention studies. Dev Med Child Neurol. 1995 Jun;37(6):473–484. [PubMed]
164. Spandou E, Soubasi V, Papoutsopoulou S, et al. Neuroprotective effect of long-term MgSO4 administration after cerebral hypoxia-ischemia in newborn rats is related to the severity of brain damage. Reprod Sci. 2007 Oct;14(7):667–677. [PubMed]
165. Khashaba MT, Shouman BO, Shaltout AA, et al. Excitatory amino acids and magnesium sulfate in neonatal asphyxia. Brain Dev. 2006 Jul;28(6):375–379. [PubMed]
166. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. Jama. 2003 Nov 26;290(20):2669–2676. [PubMed]
167. Groenendaal F, Rademaker CM, Toet MC, de Vries LS. Effects of magnesium sulphate on amplitude-integrated continuous EEG in asphyxiated term neonates. Acta Paediatr. 2002;91(10):1073–1077. [PubMed]
168. Levene M, Blennow M, Whitelaw A, Hanko E, Fellman V, Hartley R. Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 1995 Nov;73(3):F174–177. [PMC free article] [PubMed]
169. Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. Jama. 2003 Nov 26;290(20):2677–2684. [PubMed]
170. Wu YW, Colford JM., Jr Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. Jama. 2000 Sep 20;284(11):1417–1424. [PubMed]
171. Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev. 2002;8(1):46–50. [PubMed]
172. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neuroprotective agent. Neuroscientist. 2005 Aug;11(4):308–322. [PubMed]
173. Dommergues MA, Patkai J, Renauld JC, Evrard P, Gressens P. Pro-inflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann Neurol. 2000 Jan;47(1):54–63. [PubMed]
174. Dommergues MA, Plaisant F, Verney C, Gressens P. Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience. 2003;121(3):619–628. [PubMed]
175. Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000 Jul;6(7):797–801. [PubMed]
176. Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002 May 2;417(6884):74–78. [PubMed]
177. Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol. 1992 Sep 25;44(6):1165–1170. [PubMed]
178. Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7:56. [PMC free article] [PubMed]
179. Wang J, Wei Q, Wang CY, Hill WD, Hess DC, Dong Z. Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem. 2004 May 7;279(19):19948–19954. [PubMed]
180. Scarabelli TM, Stephanou A, Pasini E, et al. Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO. J Am Coll Cardiol. 2004 Mar 3;43(5):865–874. [PubMed]
181. Choi Y, Kim HS, Shin KY, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology. 2007 Nov;32(11):2393–2404. [PubMed]
182. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol. 2002 Feb;51(2):215–223. [PubMed]
183. Du Y, Ma Z, Lin S, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14669–14674. [PubMed]
184. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496–13500. [PubMed]
185. Wang CX, Yang T, Shuaib A. Effects of minocycline alone and in combination with mild hypothermia in embolic stroke. Brain Res. 2003 Feb 14;963(12):327–329. [PubMed]
186. Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol. 2002 Jul;52(1):54–61. [PubMed]
187. Fox C, Dingman A, Derugin N, et al. Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2005 Sep;25(9):1138–1149. [PMC free article] [PubMed]
188. Cai Z, Lin S, Fan LW, Pang Y, Rhodes PG. Minocycline alleviates hypoxic-ischemic injury to developing oligodendrocytes in the neonatal rat brain. Neuroscience. 2006;137(2):425–435. [PubMed]
189. Carty ML, Wixey JA, Colditz PB, Buller KM. Post-insult minocycline treatment attenuates hypoxiaischemia-induced neuroinflammation and white matter injury in the neonatal rat: a comparison of two different dose regimens. Int J Dev Neurosci. 2008 Aug;26(5):477–485. [PubMed]
190. Wasserman JK, Zhu X, Schlichter LC. Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment. Brain Res. 2007 Nov 14;1180:140–154. [PubMed]
191. Tsuji M, Wilson MA, Lange MS, Johnston MV. Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model. Exp Neurol. 2004 Sep;189(1):58–65. [PubMed]
192. Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ. Early Neurodegeneration after Hypoxia-Ischemia in Neonatal Rat Is Necrosis while Delayed Neuronal Death Is Apoptosis. Neurobiol Dis. 2001 Apr;8(2):207–219. [PubMed]
193. Portera-Cailliau C, Price DL, Martin LJ. Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis-necrosis continuum. J Comp Neurol. 1997 Feb 3;378(1):88–104. [PubMed]
194. Northington FJ, Graham EM, Martin LJ. Apoptosis in perinatal hypoxic-ischemic brain injury: how important is it and should it be inhibited? Brain Res Brain Res Rev. 2005 Dec 15;50(2):244–257. [PubMed]
195. Hu BR, Liu CL, Ouyang Y, Blomgren K, Siesjo BK. Involvement of caspase-3 in cell death after hypoxiaischemia declines during brain maturation. J Cereb Blood Flow Metab. 2000 Sep;20(9):1294–1300. [PubMed]
196. Feng Y, Fratkin JD, LeBlanc MH. Inhibiting caspase-8 after injury reduces hypoxic-ischemic brain injury in the newborn rat. Eur J Pharmacol. 2003 Nov 28;481(23):169–173. [PubMed]
197. Han BH, Xu D, Choi J, et al. Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury. J Biol Chem. 2002 Aug 16;277(33):30128–30136. [PubMed]
198. Blomgren K, Zhu C, Wang X, et al. Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of “pathological apoptosis”? J Biol Chem. 2001 Mar 30;276(13):10191–10198. [PubMed]
199. Ostwald K, Hagberg H, Andine P, Karlsson JO. Upregulation of calpain activity in neonatal rat brain after hypoxic-ischemia. Brain Res. 1993 Dec 10;630(12):289–294. [PubMed]
200. Kawamura M, Nakajima W, Ishida A, Ohmura A, Miura S, Takada G. Calpain inhibitor MDL 28170 protects hypoxic-ischemic brain injury in neonatal rats by inhibition of both apoptosis and necrosis. Brain Res. 2005 Mar 10;1037(12):59–69. [PubMed]
201. Nunez J, Yang Z, Jiang Y, Grandys T, Mark I, Levison SW. 17beta-estradiol protects the neonatal brain from hypoxia-ischemia. Exp Neurol. 2007 Dec;208(2):269–276. [PMC free article] [PubMed]
202. Hagberg H, Wilson MA, Matsushita H, et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J Neurochem. 2004 Sep;90(5):1068–1075. [PubMed]
203. Ducrocq S, Benjelloun N, Plotkine M, Ben-Ari Y, Charriaut-Marlangue C. Poly(ADP-ribose) synthase inhibition reduces ischemic injury and inflammation in neonatal rat brain. J Neurochem. 2000 Jun;74(6):2504–2511. [PubMed]
204. Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD. Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab. 1993 Jul;13(4):541–549. [PubMed]
205. Trescher WH, Ishiwa S, Johnston MV. Brief post-hypoxic-ischemic hypothermia markedly delays neonatal brain injury. Brain Dev. 1997 Jul;19(5):326–338. [PubMed]
206. Ma J, Zhang GY. Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia. Neurosci Lett. 2003 Sep 18;348(3):185–189. [PubMed]
207. Dinse A, Fohr KJ, Georgieff M, Beyer C, Bulling A, Weigt HU. Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones. Br J Anaesth. 2005 Apr;94(4):479–485. [PubMed]
208. Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol. 2004 Feb;65(2):443–452. [PubMed]
209. Ma D, Hossain M, Chow A, et al. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol. 2005 Aug;58(2):182–193. [PubMed]
210. Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke. 1989 Jul;20(7):904–910. [PubMed]
211. Hobbs C, Thoresen M, Tucker A, Aquilina K, Chakkarapani E, Dingley J. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke. 2008 Apr;39(4):1307–1313. [PubMed]
212. Khan M, Sekhon B, Jatana M, et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res. 2004 May 15;76(4):519–527. [PubMed]
213. Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK. N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res. 2003 May 2;971(1):1–8. [PubMed]
214. Jatana M, Singh I, Singh AK, Jenkins D. Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res. 2006 May;59(5):684–689. [PubMed]
215. Alkan T, Kahveci N, Buyukuysal L, Korfali E, Ozluk K. Neuroprotective effects of MK 801 and hypothermia used alone and in combination in hypoxic-ischemic brain injury in neonatal rats. Arch Physiol Biochem. 2001 Apr;109(2):135–144. [PubMed]
216. Liu Y, Barks JD, Xu G, Silverstein FS. Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke. 2004 Jun;35(6):1460–1465. [PubMed]