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1.  THE POTENTIAL FOR CELL-BASED THERAPY IN PERINATAL BRAIN INJURIES 
Translational stroke research  2013;4(2):137-148.
Perinatal brain injuries are a leading cause of cerebral palsy worldwide. The potential of stem cell therapy to prevent or reduce these impairments has been widely discussed within the medical and scientific communities and an increasing amount of research is being conducted in this field. Animal studies support the idea that a number of stem cells types, including cord blood and mesenchymal stem cells have a neuroprotective effect in neonatal hypoxia-ischemia. Both these cell types are readily available in a clinical setting. The mechanisms of action appear to be diverse, including immunomodulation, activation of endogenous stem cells, release of growth factors, and anti-apoptotic effects. Here, we review the different types of stem cells and progenitor cells that are potential candidates for therapeutic strategies in perinatal brain injuries, and summarize recent preclinical and clinical studies.
doi:10.1007/s12975-013-0254-5
PMCID: PMC3692557  PMID: 23814628
Stem Cell; Cerebral Palsy; neonate; brain injury; hypoxia ischemia
2.  Ischemia Induced Neuroinflammation is Associated with Disrupted Development of Oligodendrocyte Progenitors in a Model of Periventricular Leukomalacia 
Developmental neuroscience  2013;35(0):182-196.
Microglial activation in crossing white matter tracts is a hallmark of noncystic periventricular leukomalacia (PVL), the leading pathology underlying cerebral palsy in prematurely born infants. Recent studies indicate that neuroinflammation within an early time-window can produce long-lasting defects in oligodendroglial maturation, myelination-deficit, as well as disruption of transcription factors important in oligodendroglial maturation. We recently reported an ischemic mouse model of PVL, induced by unilateral neonatal carotid artery ligation, leading to selective long lasting bilateral myelination deficits, ipsilateral thinning of the corpus callosum, ventriculomegaly, as well as evidence of axonopathy.
Here, we report that permanent unilateral carotid ligation on postnatal day 5 (P5) in CD-1 mice induces an inflammatory response, as defined by microglial activation and recruitment, as well as significant changes in cytokine expression (increased IL-1b, IL-6, TGF-b1, and TNF-a) following ischemia. Transient reduction in counts of oligodendrocyte progenitor cells (OPCs) at 24 and 48 hours post-ischemia, a shift in OPC cell size and morphology towards the more immature form, as well as likely migration of OPCs were found. These OPC changes were topographically associated with areas showing microglial activation, and OPC counts negatively correlated with increased microglial staining.
The presented data shows a striking neuroinflammatory response in an ischemia-induced model of PVL, associated with oligodendroglial injury. Future studies modulating the neuroinflammatory response in this model, may contribute to a better understanding of the interaction between microglia and OPCs in PVL and open opportunities for future therapies.
doi:10.1159/000346682
PMCID: PMC3764456  PMID: 23445614
Infants; inflammation; ischemia; microglia; neonatal; oligodendrocyte progenitor; white matter
3.  Treatment advances in neonatal neuroprotection and neurointensive care 
Lancet neurology  2011;10(4):372-382.
Knowledge of the nature, prognosis, and ways to treat brain lesions in neonatal infants has increased remarkably. Neonatal hypoxic-ischaemic encephalopathy (HIE) in term infants, mirrors a progressive cascade of excito-oxidative events that unfold in the brain after an asphyxial insult. In the laboratory, this cascade can be blocked to protect brain tissue through the process of neuroprotection. However, proof of a clinical effect was lacking until the publication of three positive randomised controlled trials of moderate hypothermia for term infants with HIE. These results have greatly improved treatment prospects for babies with asphyxia and altered understanding of the theory of neuroprotection. The studies show that moderate hypothermia within 6 h of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurological disability by nearly 30%. The search is on to discover adjuvant treatments that can further enhance the effects of hypothermia.
doi:10.1016/S1474-4422(11)70016-3
PMCID: PMC3757153  PMID: 21435600
4.  In vivo magnetization transfer MRI shows dysmyelination in an ischemic mouse model of periventricular leukomalacia 
Periventricular leukomalacia, PVL, is the leading cause of cerebral palsy in prematurely born infants, and therefore more effective interventions are required. The objective of this study was to develop an ischemic injury model of PVL in mice and to determine the feasibility of in vivo magnetization transfer (MT) magnetic resonance imaging (MRI) as a potential monitoring tool for the evaluation of disease severity and experimental therapeutics. Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal day 5 (P5); at P60, in vivo T2-weighted (T2w) and MT-MRI were performed and correlated with postmortem histopathology. In vivo T2w MRI showed thinning of the right corpus callosum, but no significant changes in hippocampal and hemispheric volumes. Magnetization transfer MRI revealed significant white matter abnormalities in the bilateral corpus callosum and internal capsule. These quantitative MT-MRI changes correlated highly with postmortem findings of reduced myelin basic protein in bilateral white matter tracts. Ventriculomegaly and persistent astrogliosis were observed on the ligated side, along with evidence of axonopathy and fewer oligodendrocytes in the corpus callosum. We present an ischemia-induced mouse model of PVL, which has pathologic abnormalities resembling autopsy reports in infants with PVL. We further validate in vivo MRI techniques as quantitative monitoring tools that highly correlate with postmortem histopathology.
doi:10.1038/jcbfm.2011.68
PMCID: PMC3208153  PMID: 21540870
brain ischemia; glial cells; MRI; perinatal hypoxia; white matter disease
5.  Derivation of Glial Restricted Precursors from E13 mice 
This is a protocol for derivation of glial restricted precursor (GRP) cells from the spinal cord of E13 mouse fetuses. These cells are early precursors within the oligodendrocytic cell lineage. Recently, these cells have been studied as potential source for restorative therapies in white matter diseases. Periventricular leukomalacia (PVL) is the leading cause of non-genetic white matter disease in childhood and affects up to 50% of extremely premature infants. The data suggest a heightened susceptibility of the developing brain to hypoxia-ischemia, oxidative stress and excitotoxicity that selectively targets nascent white matter. Glial restricted precursors (GRP), oligodendrocyte progenitor cells (OPC) and immature oligodendrocytes (preOL) seem to be key players in the development of PVL and are the subject of continuing studies. Furthermore, previous studies have identified a subset of CNS tissue that has increased susceptibility to glutamate excitotoxicity as well as a developmental pattern to this susceptibility. Our laboratory is currently investigating the role of oligodendrocyte progenitors in PVL and use cells at the GRP stage of development. We utilize these derived GRP cells in several experimental paradigms to test their response to select stresses consistent with PVL. GRP cells can be manipulated in vitro into OPCs and preOL for transplantation experiments with mouse PVL models and in vitro models of PVL-like insults including hypoxia-ischemia. By using cultured cells and in vitro studies there would be reduced variability between experiments which facilitates interpretation of the data. Cultured cells also allows for enrichment of the GRP population while minimizing the impact of contaminating cells of non-GRP phenotype.
doi:10.3791/3462
PMCID: PMC3399460  PMID: 22760029
Neuroscience;  Issue 64;  Physiology;  Medicine;  periventricular leukomalacia;  oligodendrocytes;  glial restricted precursors;  spinal cord;  cell culture
6.  Hypoxic Ischemic Encephalopathy in the Term Infant 
Clinics in perinatology  2009;36(4):835-vii.
Synopsis
Hypoxia-ischemia in the perinatal period is an important cause of cerebral palsy and associated disabilities in children. There has been significant research progress in hypoxic-ischemic encephalopathy over the last two decades and many new molecular mechanisms have been identified. Despite all these advances, therapeutic interventions are still limited. In this review paper, we discuss a number of molecular pathways involved in hypoxia-ischemia, and potential therapeutic targets.
doi:10.1016/j.clp.2009.07.011
PMCID: PMC2849741  PMID: 19944838
Hypoxia ischemia; neonatal encephalopathy; apoptosis; oxidative stress; hypothermia
7.  QUANTITATIVE MAGNETIZATION TRANSFER CHARACTERISTICS OF THE HUMAN CERVICAL SPINAL CORD IN VIVO: APPLICATION TO ADRENOMYELONEUROPATHY 
Magnetization transfer (MT) imaging has assessed myelin integrity in the brain and spinal cord; however, quantitative MT (qMT) has been confined to the brain or excised tissue. We characterized spinal cord tissue with qMT in vivo, and as a first application, qMT-derived metrics were examined in adults with the genetic disorder Adrenomyeloneuropathy (AMN). AMN is a progressive disease marked by demyelination of the white matter tracts of the cervical spinal cord, and a disease in which conventional MRI has been limited. MT data were acquired at 1.5T using 10 radiofrequency offsets at one power in the cervical cord at C2 in 6 healthy volunteers and 9 AMN patients. The data were fit to a two-pool MT model and the macromolecular fraction (Mob), macromolecular transverse relaxation time (T2b) and the rate of MT exchange (R) for lateral and dorsal column white matter and gray matter were calculated. Mob for healthy volunteers was: WM=13.9±2.3%, GM=7.9±1.5%. In AMN, dorsal column Mob was significantly decreased (p<0.03). T2b for volunteers was: 9±2µs and the rate of MT exchange (R) was: WM=56±11Hz, GM=67±12Hz. Neither T2b nor R showed significant differences between healthy and diseased cords. Comparisons are made between qMT, and conventional MT acquisitions.
doi:10.1002/mrm.21827
PMCID: PMC2632947  PMID: 19097204
magnetization transfer; spinal cord; MT exchange; adrenomyeloneuropathy

Results 1-7 (7)