Actualities on molecular pathogenesis and repairing processes of cerebral damage in perinatal hypoxic-ischemic encephalopathy
© Distefano and Praticò; licensee BioMed Central Ltd. 2010
Received: 9 April 2010
Accepted: 16 September 2010
Published: 16 September 2010
Hypoxic-ischemic encephalopathy (HIE) is the most important cause of cerebral damage and long-term neurological sequelae in the perinatal period both in term and preterm infant.
Hypoxic-ischemic (H-I) injuries develop in two phases: the ischemic phase, dominated by necrotic processes, and the reperfusion phase, dominated by apoptotic processes extending beyond ischemic areas. Due to selective ischemic vulnerability, cerebral damage affects gray matter in term newborns and white matter in preterm newborns with the typical neuropathological aspects of laminar cortical necrosis in the former and periventricular leukomalacia in the latter.
This article summarises the principal physiopathological and biochemical processes leading to necrosis and/or apoptosis of neuronal and glial cells and reports recent insights into some endogenous and exogenous cellular and molecular mechanisms aimed at repairing H-I cerebral damage.
Hypoxic-ischemic encephalopathy (HIE) is the most important cause of cerebral damage and long-term neurological sequelae in the perinatal period both in term and preterm infant .
Until few years ago, the main acquisitions on the physiopathogenetic mechanisms of this affection came from experimental studies on animals. Recently, the progress in brain immunocytochemistry, the discovery of specific neuropathologic biochemical markers and, above all, the development of new and sophisticated techniques of nuclear magnetic resonance (NMR), i.e. diffusion weighted imaging (DWI), diffusion tensor immaging (DTI), tractography (Fibre-Tracking Techniques) and magnetic resonance spectroscopy (MRS), have collected data directly from human infants .
Besides the main role of perinatal asphyxia, a key factor in the genesis of HIE is the loss of "cerebral blood flow (CBF) autoregulation", a protective mechanism that maintains stable cerebral blood flow velocity (CBFV) in normal infants, regardless of variations of systemic arterial pressure. This mechanism is expressed by reflex modifications of cerebral arteriolar tone induced by secretion of some humoral factors with vasoconstrictive or vasodilatative action. In case of rising pressure, the release of vasoconstrictors (such as endothelin and thromboxane) that increases arteriolar resistances, reduces CBFV, while in the event of low pressure the release of vasodilators (such as prostacicline and nitric oxide) reduces arterioral resistances and increases CBFV . It has to be underlined that these autoregulator mechanisms are functionally immature in preterm infants and can be jeopardised by perinatal asphyxia due to vasoparalysis induced by increased PaCO2 and acidosis .
In presence of impaired autoregulation, CBF becomes passive to pressure stimuli. In this way, rising pressure increases CBF and can cause haemorrhagic phenomena, while low pressure reduces CBF and can cause ischemic phenomena. It has to be kept in mind that systemic arterial hypotension is frequent in high-degree premature infants who present cardiac contractile function and sympathetic vascular tone immaturity, and in all newborns with perinatal asphyxia, resulting from impaired myocardial contractility induced by hypoxia and acidosis . This explains why these infants are particularly exposed to cerebral ischemia.
Ischemia reduces CBF and thus supplies less oxygen and fewer nutrients (especially glucose, fundamental for brain energetic metabolism) and this in turn induces neural and glial cells distress triggering off cerebral damage. This is prevalently necrotic damage in cases of severe asphyxia and apoptotic in moderate asphyxia . The severity and extension of brain damage are strictly related to intensity, timing and duration of hypoxic-ischemic (H-I) insult. The more intense and long-lasting it is, the greater is the number of neuronal and glial cells which die.
Mechanisms of cerebral injury
Numerous studies show that H-I cerebral damage develops in two phases: the first or "ischemic phase" dominated by necrotic processes in the ischemic areas and the second or "reperfusion phase" dominated by apoptotic processes extending beyond ischemic areas. This second phase takes place two - six hours after H-I insult, such latency constituting a useful window in which therapeutic measures can be able to stop the evolution of cerebral damage [6, 7].
Location of injury in relation to gestational age
The location of cerebral damage differs depending on gestational age and involves primarily gray matter in term infants and white matter in prematures. This selective vulnerability of different cellular populations is related to maturational events connected to cerebral vascular system development. The neonatal encephalic regions that are more exposed to the risk of ischemia are those localized in the border zones between the end-fields of the major cerebral arteries (anterior, middle and posterior), where normal perfusion rate is basically low for the absence of anastomotic connections . These border zones, in fact, according to watershed concept (Volpe JJ, 2008) are the brain areas most susceptible to a fall in cerebral perfusion pressure. The watershed concept, based on the analogy with an irrigation system supplying a series of fields with water, emphasizes the vulnerability of the "last fields" when the head of pressure falls and have received ample experimental support in several developing animal models of hypoxic-ischemic cerebral damage .
In term infants, hypoperfused areas are localized superficially in the parasagittal cerebral regions, with ischemic injuries interesting cortical gray matter and adjacent layers of subcortical white matter. The characteristic neuropathologic aspects are represented by cortical laminar necrosis with subcortical leukomalacia.
In preterm infants, hypoperfused areas involve periventricular white matter regions. Therefore, in these subjects the classical neuropathologic aspect is that of periventricular leukomalacia (PVL), where damaged cells are made up of immature oligodendrocytes or premyelinating oligodendrocytes (pre-OLs) that ensheath axons in preparation for full differentiation to myelin-producing oligodendrocytes . In preterm newborns, in addition to the peculiarity of periventricular arterial vascularisation, PVL is also favoured by other factors related to prematurity such as metabolic hyperactivity of periventricular encephalic areas - where intense processes of proliferation, differentiation and migration of glial and neuronal cells occur, raising oxygen and nutrients demand - and, above all, the particular vulnerability of immature oligodendrocytes to the oxidative stress due to their poor content of anti-oxidizing enzymes [18, 19]. Another important role is played by the lack of neuroprotective factors such as neurotrophines and oligotrophines that are trophic substances capable of supporting brain development and inhibiting apoptotic phenomena. In the first phases of pregnancy, these factors are produced by the mother and reach the fetus through the placenta, whereas at the end of the pregnancy they are synthesized by the same fetus. Availability of such factors is therefore strongly deficient in preterm infants, especially in highly premature ones [16, 20, 21].
Neuropathology of PVL
From a pathological point of view, PVL can be distinguished in two forms: focal and diffuse. The focal form is less frequent and related to severe H-I insults. This form involves deep layers of white matter surrounding long penetrating arteries terminations and is characterized by macro or microscopic necrotic foci - where destruction of all cellular elements and axonal distruption occur - respectively evolving, over several weeks, to multiple cysts (easily visible to cranial ultrasonography) and to glial scars . The neuropathological sequelae of focal necrotic lesions are correlated with cerebral palsy (spastic diplegia) that affects 5-10% of very low birth weight infants with PVL .
Axonal disease in PVL
As white matter contains both oligodendroglial and axonal components it is still not clear whether, in diffuse PVL, H-I injuries involve only the oligodendrocytes or also the axons. While axonal damage has long been recognized as a classic feature of focal necrotic lesions [29, 30], observations of axonal injuries are only fragmentary in the diffuse form of PVL . Moreover, in a recent study on fractin, a biochemical marker of apoptosis, Haynes et al. demonstrated the presence of widespread axonal damage in non-necrotic PVL contributing to reduced white matter volume revealed by volumetric MRI in long term survivors . The cause of these axonal alterations is not yet clear, but it is probably secondary to oligodendroglial injuries. Myelinating oligodendrocytes play a critical trophic role in axonal development, survival and function, given the important effects of myelin-related proteins and OL-specific signals in long-term viability, thickness and conduction of axons [33, 34]. Therefore by compromising neurotrophic factors release, pre-OLs loss can induce failure of axonal development and/or axonal degeneration that involving, through retrograde and anterograde trans-synaptic effects, cortical-thalamic projection, commissural and association fibres lead to volume reduction of cerebral cortex and thalamus . This is mainly due to the fact that axonal alterations affect "subplate neurons", a transient population of neurons that are abundant in cerebral white matter, reach a maximum during the peak period for the occurrence of PVL (24-32 weeks of gestation) and play a crucial role in the development of the thalamus and brain cortex [36–38] (Figure 4). Volumetric MRI analyses of preterm infants with diffuse PVL, at term-equivalent age or older, have shown that, besides cortex and thalamus, volume reduction can involve other neuronal structures such as basal ganglia, cerebellum and brain stem [39, 40]. Recent neuropathological studies showed that volumetric reduction of these structures was consistent with the finding of neuronal loss and gliotic processes [22, 41]. These observations postulate the presence of a more complex "neuronal/axonal disease" accompanying oligodendroglial lesions in diffuse PVL. Therefore, the previously reported widespread axonopathy observed in non-necrotic PVL could be, to some extent, expression of degenerative processes secondary to primitive death of neuronal cell bodies in the gray matter of cortical and subcortical structures (especially the thalamus whose axons project to and from the cerebral cortex). Axonal impairment is suggested by NMR studies utilizing DTI which, in various fibre tracts of premature infants with non cystic PVL, as early as term equivalent age, showed a diminished relative anisotropy, an MRI measure of preferred directionality of diffusion [42, 43].
Neurogenetic and gliogenetic processes after H-I injury
In this field of researches related to the possibility of repairing damaged cerebral structures, studies utilizing some pluripotent cells discovered in the stroma of adipose tissue of mice, rats, non human primates and humans are intriguing. These adipose stromal cells (ASC) can exhibit differentiation into neural and glial elements in vivo and in vitro and are capable of secreting potent neurotrophic factors . In a rat middle cerebral artery occlusion model of ischemic brain injury, Kang et al  observed that intracerebral transplantation of human ASC was followed by migration of these cells to areas of ischemic damage and by expression of neuronal specific markers in conjunction with functional benefit. Therefore, therapeutic ASC could be an opportunity for developing treatments that will reverse or prevent the effects of H-I injury. Their clinical use, however, is strongly limited by the existence of the blood-brain barrier (BBB) that makes the human brain refractory to targeting of cell-sized agents delivered through the peripheral system. As intracerebral transplantation for bypassing BBB is a very invasive delivery method that cannot be proposed for human newborns, recently Wei et al. have designed a study to evaluate whether the same beneficial effects against H-I brain damage could be obtained with the neurotrophic factors secreted by ASC during culture, delivered through the peripheral venous system both preceding and following H-I injury . Their results, obtained in a rat model of H-I injury, showed that infusion (1 hour before or 24 hours after injury induction) of concentrated medium (CM) from cultured ASC (ASC-CM) significantly protected against the hippocampal and cortical volume loss observed in controls. Moreover, analysis of parallel groups for behavioural and learning changes at 2 months post-ischemia demonstrated that rats treated with ASC-CM performed significantly better than controls in Morris water maze functional tests commonly used for studying spatial learning in the rat . These positive effects of ASC-CM are not surprising because the cultural milieu of ASC was rich in neurotrophic factors, particularly insulin like growth factor-1 (IGF-1) and brain derived neurotrophic factor (BDNF) which, respectively, protect against cerebral cells apoptosis and glutamate-excitotoxicity [55–57]. In non published data, the same authors  found that equal neuroprotective activity in vitro was exhibited by ASC-CM derived from human ASC, this suggesting its potential and positive utilization in preventing or attenuating neonatal HIE. In addition to beneficial effects connected to antiapoptotic mechanisms, some factors produced by ASC may be involved in the recovery of damaged tissues stimulating migration, homing and differentiation of brain progenitor cells resident in SVZ. This approach could be an interesting way to stimulate endogenous repair without the need for targeting donor cells to the brain. Such hypothesis is supported by the recent discovery of some substances, i.e. 1alpha/CXC chemokine and nerve growth factor able to stimulate proliferation, homing and differentiation of resident neural progenitor cells in adults with cerebral injuries[58, 59].
If all these observations are confirmed by further systematic studies in the coming years, it is possible to speculate that, intravenous delivery of the milieu of factors secreted by ASC at 24-72 hours after H-I injury may represent a new promising therapeutic strategy for treatment of human neonatal HIE in addition to hypothermia that, currently, represents the most efficacious option for preventing or attenuating cerebral damage .
The authors would like to thank Mr N. Bonanno for his technical collaboration
- du Plessis AJ, Volpe JJ: Perinatal brain injury in the preterm and term newborn. Curr Opin Neurol. 2002, 15: 151-157. 10.1097/00019052-200204000-00005.PubMedView ArticleGoogle Scholar
- Hüppi PS, Dubois J: Diffusion tensor imaging of brain development. Semin Fetal Neonatal Med. 2006, 11: 489-497. 10.1016/j.siny.2006.07.006.PubMedView ArticleGoogle Scholar
- du Plessis AJ: Cerebrovascular injury in premature infants: current understanding and challenges for future prevention. Clin Perinatol. 2008, 35: 609-641. 10.1016/j.clp.2008.07.010.PubMedView ArticleGoogle Scholar
- Hüppi PS, Amato M: Advanced magnetic resonance imaging techniques in perinatal brain injury. Biol Neonate. 2001, 80: 7-14.PubMedGoogle Scholar
- Distefano G, Sciacca P, Mattia C, Betta P, Falsaperla R, Romeo MG, Amato M: Troponin I as a biomarker of cardiac injury in neonates with idiopathic respiratory distress. Am J Perinatol. 2006, 23: 229-232. 10.1055/s-2006-939537.PubMedView ArticleGoogle Scholar
- Hammerman C, Kaplan M: Ischemia and reperfusion injury. The ultimate pathophysiologic paradox. Clin Perinatol. 1998, 25: 757-777.PubMedGoogle Scholar
- Inder TE, Volpe JJ: Mechanisms of perinatal brain injury. Semin Neonatol. 2000, 5: 3-16. 10.1053/siny.1999.0112.PubMedView ArticleGoogle Scholar
- Verklan MT: The chilling details: hypoxic-ischemic encephalopathy. J Perinat Neonatal Nurs. 2009, 23: 59-68.PubMedView ArticleGoogle Scholar
- Fatemi A, Wilson MA, Johnston MV: Hypoxic-ischemic encephalopathy in the term infant. Clin Perinatol. 2009, 36: 835-858. 10.1016/j.clp.2009.07.011.PubMed CentralPubMedView ArticleGoogle Scholar
- Shouman BO, Mesbah A, Aly H: Iron metabolism and lipid peroxidation products in infants with hypoxic ischemic encephalopathy. J Perinatol. 2008, 28: 487-491. 10.1038/jp.2008.22.PubMedView ArticleGoogle Scholar
- Groenendaal F, Shadid M, McGowan JE, Mishra OP, van Bel F: Effects of deferoxamine, a chelator of free iron, on NA(+), K(+)-ATPase activity of cortical brain cell membrane during early reperfusion after hypoxia-ischaemia in newborn lambs. Pediatr Res. 2000, 48: 560-564. 10.1203/00006450-200010000-00023.PubMedView ArticleGoogle Scholar
- Fritz KI, Delivoria-Papadopoulos M: Mechanisms of injury to the newborn brain. Clin Perinatol. 2006, 33: 573-591. 10.1016/j.clp.2006.06.012.PubMedView ArticleGoogle Scholar
- Gill MB, Bockhorst K, Narayana P, Perez-Polo JR: Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects. J Neurosci Res. 2008, 86: 3584-3604. 10.1002/jnr.21795.PubMed CentralPubMedView ArticleGoogle Scholar
- Kumar A, Mittal R, Khanna HD, Basu S: Free radical injury and blood-brain barrier permeability in hypoxic-ischemic encephalopathy. Pediatrics. 2008, 122: e722-e727. 10.1542/peds.2008-0269.PubMedView ArticleGoogle Scholar
- Gluckman PD, Pinal CS, Gunn AJ: Hypoxic-ischemic brain injury in the newborn: pathophysiology and potential strategies for intervention. Semin Neonatol. 2001, 6: 109-120. 10.1053/siny.2001.0042.PubMedView ArticleGoogle Scholar
- Volpe JJ: Neurology of the newborn. 2008, Philadelphia: Elsevier, 5Google Scholar
- Scafidi J, Gallo V: New concepts in perinatal hypoxia ischemia encephalopathy. Curr Neurol Neurosci Rep. 2008, 8: 130-138. 10.1007/s11910-008-0021-2.PubMedView ArticleGoogle Scholar
- Volpe JJ: Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res. 2001, 50: 553-562. 10.1203/00006450-200111000-00003.PubMedView ArticleGoogle Scholar
- Alvarez-Díaz A, Hilario E, de Cerio FG, Valls-i-Soler A, Alvarez-Díaz FJ: Hypoxic-ischemic injury in the immature brain - Key vascular and cellular players. Neonatology. 2007, 92: 227-235. 10.1159/000103741.PubMedView ArticleGoogle Scholar
- Chouthai NS, Sampers J, Desai N, Smith GM: Changes in neurotrophin levels in umbilical cord blood from infants with different gestational ages and clinical conditions. Pediatr Res. 2003, 53: 965-969. 10.1203/01.PDR.0000061588.39652.26.PubMedView ArticleGoogle Scholar
- Malamitsi-Puchner A, Economous E, Rigopoulou O, Boutsikou T: Perinatal changes of brain-derived neurotrophic factor in pre- and full term neonates. Early Hum Dev. 2004, 76: 17-22. 10.1016/j.earlhumdev.2003.10.002.PubMedView ArticleGoogle Scholar
- Pierson CR, Folkerth RD, Billiards SS, Trachtenberg FL, Drinkwater ME, Volpe JJ, Kinney HC: Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol. 2007, 114: 619-631. 10.1007/s00401-007-0295-5.PubMed CentralPubMedView ArticleGoogle Scholar
- Volpe JJ: Cerebral white matter injury of the premature infant - More common than you think. Pediatrics. 2003, 112: 176-180. 10.1542/peds.112.1.176.PubMedView ArticleGoogle Scholar
- Dyet LE, Kennea N, Counsell SJ, Maalouf EF, Ajayi-Obe M, Duggan PJ, Harrison MA, Edwards AD: Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment. Pediatrics. 2006, 118: 536-548. 10.1542/peds.2005-1866.PubMedView ArticleGoogle Scholar
- Huppi PS: Advances in postnatal neuroimaging: relevance to pathogenesis and treatment of brain injury. Clin Perinatol. 2002, 29: 827-856. 10.1016/S0095-5108(02)00049-0.PubMedView ArticleGoogle Scholar
- Kwhaja O, Volpe JJ: Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal. 2008, 93: F153-F161.Google Scholar
- Kaur C, Ling EA: Periventricular white matter damage in the hypoxic neonatal brain: role of microglial cells. Prog Neurobiol. 2009, 87: 264-280. 10.1016/j.pneurobio.2009.01.003.PubMedView ArticleGoogle Scholar
- Damman O, O'Shea TM: Cytokines and perinatal brain damage. Clin Perinatol. 2008, 35: 643-663. 10.1016/j.clp.2008.07.011.View ArticleGoogle Scholar
- Deguchi K, Oguchi K, Takashima S: Characteristics neuropathology of leukomalacia in extremely low birth weight infants. Pediatr Neurol. 1997, 16: 296-300. 10.1016/S0887-8994(97)00041-6.PubMedView ArticleGoogle Scholar
- Hirayama A, Okoshi Y, Hachiya Y, Ozawa Y, Ito M, Kida Y, Imai Y, Kohsaka S, Takashima S: Early immunohistochemical detection of axonal damage and glial activation in extremely immature brains with periventricular leukomalacia. Clin Neuropathol. 2001, 20: 87-91.PubMedGoogle Scholar
- Dammann O, Hagberg H, Leviton A: Is periventricular leukomalacia an axonopathy as well as an oligopathy?. Pediatr Res. 2001, 49: 453-457. 10.1203/00006450-200104000-00003.PubMedView ArticleGoogle Scholar
- Haynes RL, Billiards SS, Borenstein NS, Volpe JJ, Kinney HC: Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin. Pediatr Res. 2008, 63: 656-661. 10.1203/PDR.0b013e31816c825c.PubMed CentralPubMedView ArticleGoogle Scholar
- Bjartmar C, Yin X, Trapp BD: Axonal pathology in myelin disorders. J Neurocytol. 1999, 28: 383-395. 10.1023/A:1007010205037.PubMedView ArticleGoogle Scholar
- Roy K, Murtie JC, El-Khodor BF, Edgar N, Sardi SP, Hooks BM, Benoit-Marand M, Chen C, Moor H, O'Donnel P, Brunner D, Corfas G: Loss of erbB signaling in oligodendrocytes alter myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci USA. 2007, 104: 8131-8136. 10.1073/pnas.0702157104.PubMed CentralPubMedView ArticleGoogle Scholar
- Du YZ, Dreyfus CF: Oligodendrocytes as providers of growth factors. J Neurosci. 2002, 68: 647-654. 10.1002/jnr.10245.Google Scholar
- Volpe JJ: Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009, 8: 110-124. 10.1016/S1474-4422(08)70294-1.PubMed CentralPubMedView ArticleGoogle Scholar
- Bystron I, Blakemore C, Rakic P: Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci. 2008, 9: 110-122. 10.1038/nrn2252.PubMedView ArticleGoogle Scholar
- Ghosh A, Shatz CJ: A role for subplate neurons in the patterning of connections from thalamus to neocortex. Development. 1993, 117: 1031-1047.PubMedGoogle Scholar
- Kesler SR, Ment LR, Vohr B, Pajot SK, Schneider KC, Katz KH, Ebbitt TB, Duncan CC, Makuch RW, Reiss AL: Volumetric analysis of regional cerebral development in preterm children. Pediatr Neurol. 2004, 31: 318-325. 10.1016/j.pediatrneurol.2004.06.008.PubMed CentralPubMedView ArticleGoogle Scholar
- Srinivasan L, Dutta R, Counsell SJ, Allsop JM, Boardman JP, Rutherford MA, Edwards AD: Quantification of deep gray matter in preterm infants at term-equivalent age using manual volumetry of 3-tesla magnetic resonance images. Pediatrics. 2007, 119: 759-765. 10.1542/peds.2006-2508.PubMedView ArticleGoogle Scholar
- Ligam P, Haynes RL, Folkerth D, Liu L, Yang M, Volpe JJ, Kinney HC: Thalamic damage in periventricular leukomalacia: novel pathologic observations relevant to cognitive deficits in survivors of prematurity. Pediatr Res. 2009, 65: 524-529. 10.1203/PDR.0b013e3181998baf.PubMed CentralPubMedView ArticleGoogle Scholar
- Huppi PS, Murphy B, Maier SE, Zientara GP, Inder TE, Barnes PD, Kikinis R, Jolesz FA, Volpe JJ: Microstructural brain development after perinatal cerebral white matter injury assesed by diffusion tensor magnetic resonance imaging. Pediatrics. 2001, 107: 455-460. 10.1542/peds.107.3.455.PubMedView ArticleGoogle Scholar
- Counsell SH, Shen Y, Boardman JP, Larkman DJ, Kapellou O, Ward P, Allsop JM, Cowan FM, Hajnal JV, Edwards AD, Rutherford MA: Axial and radial diffusivity in preterm infants who have diffuse white matter changes on magnetic resonance imaging at term-equivalent age. Pediatrics. 2006, 117: 376-386. 10.1542/peds.2005-0820.PubMedView ArticleGoogle Scholar
- Di Iorio R, Marinoni E, Letizia C, Gazzolo D, Lucchini C, Cosmi EV: Adrenomedullin is increased in the fetoplacental circulation in intrauterine growth restriction with abnormal umbilical artery waveforms. Am J Obstet Gynecol. 2000, 182: 650-654. 10.1067/mob.2000.103944.PubMedView ArticleGoogle Scholar
- Nagdyman N, Grimmer I, Scholz T, Muller C, Obladen M: Predictive value of brain-specific proteins in serum for neurodevelopmental outcome after birth asphyxia. Pediatr Res. 2003, 54: 270-275. 10.1203/01.PDR.0000072518.98189.A0.PubMedView ArticleGoogle Scholar
- Buonocore G, Perrone S: Biomarkers of hypoxic brain injury in the neonate. Clin Perinatol. 2004, 31: 107-116. 10.1016/j.clp.2004.03.008.PubMedView ArticleGoogle Scholar
- Gazzolo D, Abella R, Marinoni E, Di Iorio R, Li Volti G, Galvano F, Pongiglione G, Frigiola A, Bertino E, Florio P: Circulating biochemical markers of brain damage in infants complicated by ischemia reperfusion injury. Cardiovasc Hematol Agents Med Chem. 2009, 7: 108-126. 10.2174/187152509787847119.PubMedView ArticleGoogle Scholar
- Florio P, Frigiola A, Battista R, Abdalla Ael H, Gazzolo D, Galleri L, Pinzauti S, Abella R, Li Volti G, Strambi M: Activin A in asphyxiated full-term newborns with hypoxic ischemic encephalopathy. Front Biosci (Elite Ed). 2010, 2: 36-42. 10.2741/e62.View ArticleGoogle Scholar
- Distefano G, Curreri S, Betta P, Li Volti G, Cilauro S, Frigiola A, Huppi P, Amato M: Perinatal asphyxia in preterm neonates leads to serum changes in protein S-100 and neuron specific enolase. Curr Neurovasc Res. 2009, 6: 110-116. 10.2174/156720209788185614.View ArticleGoogle Scholar
- Yang Z, Levison SW: Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. Neuroscience. 2006, 139: 555-564. 10.1016/j.neuroscience.2005.12.059.PubMedView ArticleGoogle Scholar
- Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, Gimble JM, Rice HE: Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun. 2002, 294: 371-379. 10.1016/S0006-291X(02)00469-2.PubMedView ArticleGoogle Scholar
- Kang SK, Lee DH, Bae YC, Kim HK, Baik SY, Jung JS: Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats. Exp Neurol. 2003, 183: 355-366. 10.1016/S0014-4886(03)00089-X.PubMedView ArticleGoogle Scholar
- Wei X, Du Z, Zhao L, Feng D, Wei G, He Y, Tan J, Lee WH, Hampel H, Dodel R, Johnstone BH, March KL, Farlow MR, Du Y: IFATS series: the conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells. 2009, 27: 478-488. 10.1634/stemcells.2008-0333.PubMedView ArticleGoogle Scholar
- Morris R: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984, 11: 47-60. 10.1016/0165-0270(84)90007-4.PubMedView ArticleGoogle Scholar
- Yamagishi S, Matsumoto T, Yokomaku D, Hatanaka H, Shimoke K, Yamada M, Ikeuchi T: Comparison of inhibitory effects of brain-derived neurotrophic factor and insulin-like growth factor on low potassium-induced apoptosis and activation of p38 MAPK and c-Jun in cultured cerebellar granule neurons. Brain Res Mol Brain Res. 2003, 119: 184-191. 10.1016/j.molbrainres.2003.09.009.PubMedView ArticleGoogle Scholar
- Brywe KG, Mallard C, Gustavsson M, Hedtjärn M, Leverin AL, Wang X, Blomgren K, Isgaard J, Hagberg H: IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?. Eur J Neurosci. 2005, 21: 1489-1502. 10.1111/j.1460-9568.2005.03982.x.PubMedView ArticleGoogle Scholar
- Almeida RD, Manadas BJ, Melo CV, Gomes JR, Mendes CS, Grãos MM, Carvalho RF, Carvalho AP, Duarte CB: Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ. 2005, 12: 1329-1343. 10.1038/sj.cdd.4401662.PubMedView ArticleGoogle Scholar
- Imitola J, Raddassi K, Park KI: 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 USA. 2004, 101: 18117-18122. 10.1073/pnas.0408258102.PubMed CentralPubMedView ArticleGoogle Scholar
- Jin K, Galvan V: Endogenous neural stem cells in the adult brain. J Neuroimmune Pharmacol. 2007, 2: 236-242. 10.1007/s11481-007-9076-0.PubMedView ArticleGoogle Scholar
- Edwards AD: The discovery of hypothermic neural rescue therapy for perinatal hypoxic-ischemic encephalopathy. Semin Pediatr Neurol. 2009, 16: 200-206. 10.1016/j.spen.2009.09.007.PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.