Publications by authors named "Zinaida S Vexler"

49 Publications

Mesenchymal Stem Cell (MSC)-Derived Extracellular Vesicles Protect from Neonatal Stroke by Interacting with Microglial Cells.

Neurotherapeutics 2021 Jul 7. Epub 2021 Jul 7.

Department of Neurology, UCSF, 675 Nelson Rising Lane, San Francisco, CA, 94158-0663, USA.

Mesenchymal stem cell (MSC)-based therapies are beneficial in models of perinatal stroke and hypoxia-ischemia. Mounting evidence suggests that in adult injury models, including stroke, MSC-derived small extracellular vesicles (MSC-sEV) contribute to the neuroprotective and regenerative effects of MSCs. Herein, we examined if MSC-sEV protect neonatal brain from stroke and if this effect is mediated via communication with microglia. MSC-sEV derived from bone marrow MSCs were characterized by size distribution (NanoSight™) and identity (protein markers). Studies in microglial cells isolated from the injured or contralateral cortex of postnatal day 9 (P9) mice subjected to a 3-h middle cerebral artery occlusion (tMCAO) and cultured (in vitro) revealed that uptake of fluorescently labeled MSC-sEV was significantly greater by microglia from the injured cortex vs. contralateral cortex. The cell-type-specific spatiotemporal distribution of MSC-sEV was also determined in vivo after tMCAO at P9. MSC-sEV administered at reperfusion, either by intracerebroventricular (ICV) or by intranasal (IN) routes, accumulated in the hemisphere ipsilateral to the occlusion, with differing spatial distribution 2 h, 18 h, and 72 h regardless of the administration route. By 72 h, MSC-sEV in the IN group was predominantly observed in Iba1 cells with retracted processes and in GLUT1 blood vessels in ischemic-reperfused regions. MSC-sEV presence in Iba1 cells was sustained. MSC-sEV administration also significantly reduced injury volume 72 h after tMCAO in part via modulatory effects on microglial cells. Together, these data establish feasibility for MSC-sEV delivery to injured neonatal brain via a clinically relevant IN route, which affords protection during sub-acute injury phase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-021-01076-9DOI Listing
July 2021

Neonatal stroke enhances interaction of microglia-derived extracellular vesicles with microglial cells.

Neurobiol Dis 2021 Jun 18:105431. Epub 2021 Jun 18.

Department of Neurology, UCSF, San Francisco, CA, USA. Electronic address:

Microglial cells support brain homeostasis under physiological conditions and modulate brain injury in a context-dependent and brain maturation-dependent manner. Microglial cells protect neonatal brain from acute stroke. While microglial signaling via direct cell-cell interaction and release of variety of molecules is intensely studied, less is known about microglial signaling via release and uptake of extracellular vesicles (EVs). We asked whether neonatal stroke alters release of microglial EVs (MEV) and MEV communication with activated microglia. We pulled down and plated microglia from ischemic-reperfused and contralateral cortex 24 h after transient middle cerebral artery occlusion (tMCAO) in postnatal day 9 mice, isolated and characterized microglia-derived microvesicles (P3-MEV) and exosomes (P4-MEV), and determined uptake of fluorescently labeled P3-MEV and P4-MEV by plated microglia derived from ischemic-reperfused and contralateral cortex. We then examined how reducing EVs release in neonatal brain-by intra-cortical injection of CRISPR-Cas9-Smpd3/KO (Smpd3/KD) to downregulate Smpd3 gene to disrupt neutral sphingomyelinase-2 (N-SMase2)-impacts P3-MEV and P4-MEV release and stroke injury. Both size and protein composition differed between P3-MEV and P4-MEV. tMCAO further altered protein composition of P3-MEV and P4-MEV and significantly, up to 5-fold, increased uptake of both vesicle subtypes by microglia from ischemic-reperfused regions. Under physiological conditions neurons were the predominant cell type expressing N-SMase-2, an enzyme involved in lipid signaling and EVs release. After tMCAO N-SMase-2 expression was diminished in injured neurons but increased in activated microglia/macrophages, leading to overall reduced N-SMase-2 activity. Compared to intracerebral injection of control plasmid, CRISPR-Cas9-Smpd3/Ct, Smpd3/KD injection further reduced N-SMase-2 activity and significantly reduced injury. Smpd3 downregulation decreased MEV release from injured regions, reduced Smpd3/KD-P3-MEV uptake and abolished Smpd3/KD-P4-MEV uptake by microglia from ischemic-reperfused region. Cumulatively, these data demonstrate that microglial cells release both microvesicles and exosomes in naïve neonatal brain, that the state of microglial activation determines both properties of released EVs and their recognition/uptake by microglia in ischemic-reperfused and control regions, suggesting a modulatory role of MEV in neonatal stroke, and that sphingosine/N-SMase-2 signaling contributes both to EVs release and uptake (predominantly P4-MEV) after neonatal stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2021.105431DOI Listing
June 2021

Microglia-leucocyte axis in cerebral ischaemia and inflammation in the developing brain.

Acta Physiol (Oxf) 2021 May 15:e13674. Epub 2021 May 15.

Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Development of the Central Nervous System (CNS) is reliant on the proper function of numerous intricately orchestrated mechanisms that mature independently, including constant communication between the CNS and the peripheral immune system. This review summarizes experimental knowledge of how cerebral ischaemia in infants and children alters physiological communication between leucocytes, brain immune cells, microglia and the neurovascular unit (NVU)-the "microglia-leucocyte axis"-and contributes to acute and long-term brain injury. We outline physiological development of CNS barriers in relation to microglial and leucocyte maturation and the plethora of mechanisms by which microglia and peripheral leucocytes communicate during postnatal period, including receptor-mediated and intracellular inflammatory signalling, lipids, soluble factors and extracellular vesicles. We focus on the "microglia-leucocyte axis" in rodent models of most common ischaemic brain diseases in the at-term infants, hypoxic-ischaemic encephalopathy (HIE) and focal arterial stroke and discuss commonalities and distinctions of immune-neurovascular mechanisms in neonatal and childhood stroke compared to stroke in adults. Given that hypoxic and ischaemic brain damage involve Toll-like receptor (TLR) activation, we discuss the modulatory role of viral and bacterial TLR2/3/4-mediated infection in HIE, perinatal and childhood stroke. Furthermore, we provide perspective of the dynamics and contribution of the axis in cerebral ischaemia depending on the CNS maturational stage at the time of insult, and modulation independently and in consort by individual axis components and in a sex dependent ways. Improved understanding on how to modify crosstalk between microglia and leucocytes will aid in developing age-appropriate therapies for infants and children who suffered cerebral ischaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apha.13674DOI Listing
May 2021

Neonatal Stroke and TLR1/2 Ligand Recruit Myeloid Cells through the Choroid Plexus in a CX3CR1-CCR2- and Context-Specific Manner.

J Neurosci 2020 05 8;40(19):3849-3861. Epub 2020 Apr 8.

Department of Neurology, University of California San Francisco, San Francisco, California 94158

Neonatal stroke is as frequent as stroke in the elderly, but many pathophysiological injury aspects are distinct in neonates, including immune signaling. While myeloid cells can traffic into the brain via multiple routes, the choroid plexus (CP) has been identified as a uniquely educated gate for immune cell traffic during health and disease. To understand the mechanisms of myeloid cell trafficking via the CP and their influence on neonatal stroke, we characterized the phenotypes of CP-infiltrating myeloid cells after transient middle cerebral artery occlusion (tMCAO) in neonatal mice of both sexes in relation to blood-brain barrier permeability, injury, microglial activation, and CX3CR1-CCR2 signaling, focusing on the dynamics early after reperfusion. We demonstrate rapid recruitment of multiple myeloid phenotypes in the CP ipsilateral to the injury, including inflammatory CD45CD11bLy6cCD86, beneficial CD45CD11bLy6cCD206, and CD45CD11bLy6cLy6g cells, but only minor leukocyte infiltration into acutely ischemic-reperfused cortex and negligible vascular albumin leakage. We report that CX3CR1-CCR2-mediated myeloid cell recruitment contributes to stroke injury. Considering the complexity of inflammatory cascades triggered by stroke and a role for TLR2 in injury, we also used direct TLR2 stimulation as an independent injury model. TLR2 agonist rapidly recruited myeloid cells to the CP, increased leukocytosis in the CSF and blood, but infiltration into the cortex remained low over time. While the magnitude and the phenotypes of myeloid cells diverged between tMCAO and TLR2 stimulation, in both models, disruption of CX3CR1-CCR2 signaling attenuated both monocyte and neutrophil trafficking to the CP and cortex. Stroke during the neonatal period leads to long-term disabilities. The mechanisms of ischemic injury and inflammatory response differ greatly between the immature and adult brain. We examined leukocyte trafficking via the choroid plexus (CP) following neonatal stroke in relation to blood-brain barrier integrity, injury, microglial activation, and signaling via CX3CR1 and CCR2 receptors, or following direct TLR2 stimulation. Ischemia-reperfusion triggered marked unilateral CX3CR1-CCR2 dependent accumulation of diverse leukocyte subpopulations in the CP without inducing extravascular albumin leakage or major leukocyte infiltration into the brain. Disrupted CX3CR1-CCR2 signaling was neuroprotective in part by attenuating monocyte and neutrophil trafficking. Understanding the migratory patterns of CP-infiltrating myeloid cells with intact and disrupted CX3CR1-CCR2 signaling could identify novel therapeutic targets to protect the neonatal brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2149-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204080PMC
May 2020

Positive and negative conditioning in the neonatal brain.

Cond Med 2018 Oct;1(6):279-293

Center of Perinatal Medicine and Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.

Brain injury in the perinatal period occurs in many clinical settings, e.g. hypoxic-ischemic encephalopathy (HIE) in term infants, neonatal stroke, encephalopathy of prematurity, and infections. These insults often result in life-long disabilities including cerebral palsy, cognitive deficits, visual dysfunction, hearing impairments, and epilepsy. However, the success of clinical implementation of a broad array of potential neuroprotective strategies tested experimentally has been limited with the exception of therapeutic hypothermia (TH) used within hours of birth in term human babies with mild to moderate HIE. There is an extensive search for adjuvant therapeutic approaches to enhance the outcomes. One strategy is to modify susceptibility in the developing CNS by means of preconditioning or postconditioning using sublethal stress. The pre-clinical and clinical literature has shown that CNS immaturity at the time of ischemic insult plays a central role in the response to injury. Thus, better understanding of the molecular regulation of the endogenous vulnerability of the immature brain is needed. Further, the use of sublethal stressors of different origin may help shed light on mechanistic similarities and distinctions beween conditioning strategies. In this review we discuss the mechanisms of protection that are achieved by an interplay of changes on the systemic level and brain level, and via changes of intracellular and mitochondrial signaling. We also discuss the barriers to improving our understanding of how brain immaturity and the type of insult-hypoxic, ischemic or inflammatory-affect the efficacy of conditioning efforts in the immature brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581457PMC
October 2018

CX3CR1-CCR2-dependent monocyte-microglial signaling modulates neurovascular leakage and acute injury in a mouse model of childhood stroke.

J Cereb Blood Flow Metab 2019 10 10;39(10):1919-1935. Epub 2019 Jan 10.

Department of Neurology, University California San Francisco, CA, USA.

Stroke is among the top 10 causes of death in children. The developmental stage of the brain is central to stroke pathophysiology. The incidence of childhood arterial ischemic stroke (CAIS) is lower than of perinatal arterial ischemic stroke but the rate of recurrence is strikingly high. Vascular inflammation is seen as major contributor to CAIS but the mechanisms that govern structural-functional basis of vascular abnormalities remain poorly understood. To identify the contribution of immune-neurovascular interactions to CAIS, we established stroke model in postnatal day 21 (P21) mice. We demonstrate acute functional deficits and histological injury and chronic MRI-identifiable injury, brain atrophy and marked derangements in the vascular network. In contrast to negligible albumin leakage and neutrophil infiltration following acute perinatal stroke, CAIS leads to significantly increased albumin leakage and neutrophil infiltration in injured regions of wild type mice and mice with functional CX3CR1-CCR2 receptors. In mice with dysfunctional CX3CR1-CCR2 signaling, extravascular albumin leakage is significantly attenuated, infiltration of injurious Ccr2-monocytes essentially aborted, accumulation of Ly6G+ neutrophils reduced and acute injury attenuated. Unique identifiers of microglia and monocytes revealed phenotypic changes in each cell subtype of the monocyte lineage after CAIS. Taken together, CX3CR1-CCR2-dependent microglia-monocyte signaling contributes to cerebrovascular leakage, inflammation and CAIS injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0271678X18817663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775594PMC
October 2019

A Novel Technique for Visualizing and Analyzing the Cerebral Vasculature in Rodents.

Transl Stroke Res 2018 May 15. Epub 2018 May 15.

Cell, Molecular and Developmental Biology Program, University of California, Riverside, 1140 Bachelor Hall, Riverside, CA, 92521, USA.

We introduce a novel protocol to stain, visualize, and analyze blood vessels from the rat and mouse cerebrum. This technique utilizes the fluorescent dye, DiI, to label the lumen of the vasculature followed by perfusion fixation. Following brain extraction, the labeled vasculature is then imaged using wide-field fluorescence microscopy for axial and coronal images and can be followed by regional confocal microscopy. Axial and coronal images can be analyzed using classical angiographic methods for vessel density, length, and other features. We also have developed a novel fractal analysis to assess vascular complexity. Our protocol has been optimized for adult rat, adult mouse, and neonatal mouse studies. The protocol is efficient, can be rapidly completed, stains cerebral vessels with a bright fluorescence, and provides valuable quantitative data. This method has a broad range of applications, and we demonstrate its use to study the vasculature in assorted models of acquired brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12975-018-0632-0DOI Listing
May 2018

The myth of the immature barrier systems in the developing brain: role in perinatal brain injury.

J Physiol 2018 12 16;596(23):5655-5664. Epub 2018 Apr 16.

Department of Neurology, University California San Francisco, USA.

Central nervous system homeostasis is maintained by cellular barriers that protect the brain from external environmental changes and protect the CNS from harmful molecules and pathogens in the blood. Historically, for many years these barriers were thought of as immature, with limited functions, during brain development. In this review, we will present advances in the understanding of the barrier systems during development and evidence to show that in fact the barriers serve many important neurodevelopmental functions and that fetal and newborn brains are well protected. We will also discuss how ischaemic injury or systemic inflammation may breach the integrity of the barriers in the developing brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP274938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265562PMC
December 2018

Microglia and Neonatal Brain Injury.

Neuroscience 2019 05 17;405:68-76. Epub 2018 Jan 17.

Department of Neurology, University California San Francisco, United States. Electronic address:

Microglial cells are now recognized as the "gate-keepers" of healthy brain microenvironment with their disrupted functions adversely affecting neurovascular integrity, neuronal homeostasis, and network connectivity. The perception that these cells are purely toxic under neurodegenerative conditions has been challenged by a continuously increasing understanding of their complexity, the existence of a broad array of microglial phenotypes, and their ability to rapidly change in a context-dependent manner to attenuate or exacerbate injuries of different nature. Recent studies have demonstrated that microglial cells exert crucial physiological functions during embryonic and postnatal brain development, some of these functions being unique to particular stages of development, and extending far beyond sensing dangerous signals and serving as antigen presenting cells. In this focused review we cover the roles of microglial cells in regulating embryonic vasculogenesis, neurogenesis, and establishing network connectivity during postnatal brain development. We further discuss context-dependent microglial contribution to neonatal brain injuries associated with prenatal and postnatal infection and inflammation, in relation to neurodevelopmental disorders, as well as perinatal hypoxia-ischemia and arterial focal stroke. We also emphasize microglial phenotypic diversity, notably at the ultrastructural level, and their sex-dependent influence on the pathophysiology of neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2018.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790108PMC
May 2019

Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection.

Brain Behav Immun 2017 Oct 1;65:312-327. Epub 2017 Jun 1.

Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Research Center of the IUSMQ, 2601, de la Canardière, Québec, QC G1J 2G3, Canada. Electronic address:

Activation of microglial cells in response to brain injury and/or immune stimuli is associated with a marked induction of Toll-like receptors (TLRs). While in adult brain, the contribution of individual TLRs, including TLR2, in pathophysiological cascades has been well established, their role and spatial and temporal induction patterns in immature brain are far less understood. To examine whether infectious stimuli and sterile inflammatory stimuli trigger distinct TLR2-mediated innate immune responses, we used three models in postnatal day 9 (P9) mice, a model of infection induced by systemic endotoxin injection and two models of sterile inflammation, intra-cortical IL-1β injection and transient middle cerebral artery occlusion (tMCAO). We took advantage of a transgenic mouse model bearing the dual reporter system luciferase/GFP under transcriptional control of a murine TLR2 promoter (TLR2-luc-GFP) to visualize the TLR2 response in the living neonatal brain and then determined neuroinflammation, microglial activation and leukocyte infiltration. We show that in physiological postnatal brain development the in vivo TLR2-luc signal undergoes a marked ∼30-fold decline and temporal-spatial changes during the second and third postnatal weeks. We then show that while endotoxin robustly induces the in vivo TLR2-luc signal in the living brain and increases levels of several inflammatory cytokines and chemokines, the in vivo TLR2-luc signal is reduced after both IL-1β and tMCAO and the inflammatory response is muted. Immunofluorescence revealed that microglial cells are the predominant source of TLR2 production during postnatal brain development and in all three neonatal models studied. Flow cytometry revealed developmental changes in CD11b/CD45 and CD11b/Ly6C cell populations, involvement of cells of the monocyte lineage, but lack of Ly6G neutrophils or CD3 cells in acutely injured neonatal brains. Cumulatively, our results suggest distinct TLR2 induction patterns following PAMP and DAMP - mediated inflammation in immature brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2017.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151183PMC
October 2017

Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia-ischemia.

Pediatr Res 2017 Sep 31;82(3):518-526. Epub 2017 May 31.

Department of Pediatrics, University of California San Francisco, San Francisco, California.

BackgroundTherapeutic hypothermia (TH) is the standard of care for neonates with hypoxic-ischemic encephalopathy, but it is not fully protective in the clinical setting. Hypoxia-ischemia (HI) may cause white matter injury (WMI), leading to neurological and cognitive dysfunction.MethodsP9 mice were subjected to HI as previously described. Pups underwent 3.5 h of systemic hypothermia or normothermia. Cresyl violet and Perl's iron staining for histopathological scoring of brain sections was completed blindly on all brains. Immunocytochemical (ICC) staining for myelin basic protein (MBP), microglia (Iba1), and astrocytes (glia fibrillary acidic protein (GFAP)) was performed on adjacent sections. Volumetric measurements of MBP coverage were used for quantitative analysis of white matter.ResultsTH provided neuroprotection by injury scoring for the entire group (n=44; P<0.0002). ICC analysis of a subset of brains showed that the lateral caudate was protected from WMI (P<0.05). Analysis revealed decreased GFAP and Iba1 staining in hippocampal regions, mostly CA2/CA3. GFAP and Iba1 directly correlated with injury scores of normothermic brains.ConclusionTH reduced injury, and qualitative data suggest that hippocampus and lateral caudate are protected from HI. Mildly injured brains may better show the benefits of TH. Overall, these data indicate regional differences in WMI susceptibility and inflammation in a P9 murine HI model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/pr.2017.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570671PMC
September 2017

Genetic deletion of galectin-3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke.

Brain Behav Immun 2017 Feb 9;60:270-281. Epub 2016 Nov 9.

Department of Neurology, University California San Francisco, CA 94158-0663, USA. Electronic address:

The pathophysiology of neonatal stroke and adult stroke are distinct in many aspects, including the inflammatory response. We previously showed endogenously protective functions of microglial cells in acute neonatal stroke. We asked if galectin-3 (Gal3), a pleotropic molecule that mediates interactions between microglia/macrophages and the extracellular matrix (ECM), plays a role in early injury after transient middle cerebral occlusion (tMCAO) in postnatal day 9-10 mice. Compared to wild type (WT) pups, in Gal3 knockout pups injury was worse and cytokine/chemokine production altered, including further increase of MIP1α and MIP1β levels and reduced IL6 levels 72h after tMCAO. Lack of Gal3 did not affect morphological transformation or proliferation of microglia but markedly attenuated accumulation of CD11b/CD45 cells after injury, as determined by multi-color flow cytometry. tMCAO increased expression of αV and β integrin subunits in CD11b/CD45 microglial cells and cells of non-monocyte lineage (CD11b/CD45), but not in CD11b/CD45 cells within injured regions of WT mice or Gal3-/- mice. αV upregulated in areas occupied and not occupied by CD68 cells, most prominently in the ECM, lining blood vessels, with expanded αV coverage in Gal3-/- mice. Cumulatively, these data show that lack of Gal3 worsens subchronic injury after neonatal focal stroke, likely by altering the neuroinflammatory milieu, including an imbalance between pro- and anti-inflammatory molecules, effects on microglial activation, and deregulation of the composition of the ECM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2016.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909718PMC
February 2017

Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats.

J Neurosci Res 2017 05 26;95(5):1225-1236. Epub 2016 Oct 26.

Department of Neurology, University of California, San Francisco, San Francisco, California.

Cell therapy has emerged as a potential treatment for many neurodegenerative diseases including stroke and neonatal ischemic brain injury. Delayed intranasal administration of mesenchymal stem cells (MSCs) after experimental hypoxia-ischemia and after a transient middle cerebral artery occlusion (tMCAO) in neonatal rats has shown improvement in long-term functional outcomes, but the effects of MSCs on white matter injury (WMI) are insufficiently understood. In this study we used longitudinal T2-weighted (T2W) and diffusion tensor magnetic resonance imaging (MRI) to characterize chronic injury after tMCAO induced in postnatal day 10 (P10) rats and examined the effects of delayed MSC administration on WMI, axonal coverage, and long-term somatosensory function. We show unilateral injury- and region-dependent changes in diffusion fraction anisotropy 1 and 2 weeks after tMCAO that correspond to accumulation of degraded myelin basic protein, astrocytosis, and decreased axonal coverage. With the use of stringent T2W-based injury criteria at 72 hr after tMCAO to randomize neonatal rats to receive intranasal MSCs or vehicle, we show that a single MSC administration attenuates WMI and enhances somatosensory function 28 days after stroke. A positive correlation was found between MSC-enhanced white matter integrity and functional performance in injured neonatal rats. Collectively, these data indicate that the damage induced by tMCAO progresses over time and is halted by administration of MSCs. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.23954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352529PMC
May 2017

Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke.

J Neurosci 2016 Mar;36(10):2881-93

Department of Neurology, University of California-San Francisco, San Francisco, California 94158,

Perinatal stroke leads to significant morbidity and long-term neurological and cognitive deficits. The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. To understand whether microglial cells limit injury after neonatal stroke by preserving neurovascular integrity, we subjected postnatal day 7 (P7) rats depleted of microglial cells, rats with inhibited microglial TGFbr2/ALK5 signaling, and corresponding controls, to transient middle cerebral artery occlusion (tMCAO). Microglial depletion by intracerebral injection of liposome-encapsulated clodronate at P5 significantly reduced vessel coverage and triggered hemorrhages in injured regions 24 h after tMCAO. Lack of microglia did not alter expression or intracellular redistribution of several tight junction proteins, did not affect degradation of collagen IV induced by the tMCAO, but altered cell types producing TGFβ1 and the phosphorylation and intracellular distribution of SMAD2/3. Selective inhibition of TGFbr2/ALK5 signaling in microglia via intracerebral liposome-encapsulated SB-431542 delivery triggered hemorrhages after tMCAO, demonstrating that TGFβ1/TGFbr2/ALK5 signaling in microglia protects from hemorrhages. Consistent with observations in neonatal rats, depletion of microglia before tMCAO in P9 Cx3cr1(GFP/+)/Ccr2(RFP/+) mice exacerbated injury and induced hemorrhages at 24 h. The effects were independent of infiltration of Ccr2(RFP/+) monocytes into injured regions. Cumulatively, in two species, we show that microglial cells protect neonatal brain from hemorrhage after acute ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0140-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783493PMC
March 2016

Modeling Ischemia in the Immature Brain: How Translational Are Animal Models?

Stroke 2015 Oct 13;46(10):3006-11. Epub 2015 Aug 13.

From the Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden (C.M.); and Department of Neurology, University California San Francisco (Z.S.V.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.115.007776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589478PMC
October 2015

Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke.

J Neurochem 2015 Nov 3;135(3):445-52. Epub 2015 Sep 3.

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

The stage of brain development at the time of stroke has a major impact on the pathophysiological mechanisms of ischemic damage, including the neuroinflammatory response. Microglial cells have been shown to contribute to acute and subchronic injury in adult stroke models, whereas in neonatal rodents we showed that microglial cells serve as endogenous neuroprotectants early following transient middle cerebral artery occlusion, limiting neuroinflammation and injury. In the neonate, microglial depletion or lack of the scavenger receptor CD36 exacerbates injury. In this study we asked if lack of CD36 affects microglial phenotypes after neonatal stroke. Using RT-PCR we characterized the patterns of gene expression in microglia isolated from injured regions following acute transient middle cerebral artery occlusion in postnatal day 10 mice and showed that expression of several pro-inflammatory genes, including Toll-like receptors, remains largely unaffected in activated microglia in injured regions. Using multiple biochemical assays we demonstrated that lack of CD36 alters several functions of microglia in acutely injured neonatal brain: it further enhances accumulation of the chemokine MCP-1, affects the number of CD11b(+) /CD45(+) cells, along with protein expression of its co-receptor, Toll-like receptor 2, but does not affect accumulation of superoxide in microglia or the cytokines TNFα and IL-1β in injured regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.13239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844456PMC
November 2015

Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models.

Pediatr Neurol 2015 Jun 31;52(6):566-584. Epub 2015 Jan 31.

Inserm, U1141, F-75019 Paris, France.

Background: Arterial ischemic stroke occurs more frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared with childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. Our understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many factors remain incompletely understood.

Methods: In this review, we focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment.

Results: Studies in neonatal rodent models of cerebral ischemia have suggested a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort is underway to investigate neuroprotective molecules based on our increasing understanding of the pathophysiology.

Conclusion: In this review, we provide a comprehensive summary of new insights concerning pathophysiology of focal and global perinatal brain injury and their implications for new therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720385PMC
June 2015

LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.

J Cell Biol 2015 Mar 9;208(6):703-11. Epub 2015 Mar 9.

Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093

The blood-brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.201410131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362448PMC
March 2015

The role of inflammation in perinatal brain injury.

Nat Rev Neurol 2015 Apr 17;11(4):192-208. Epub 2015 Feb 17.

Inserm, U1141, Paris 75019, France.

Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development. Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity. Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrneurol.2015.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664161PMC
April 2015

Barrier mechanisms in neonatal stroke.

Front Neurosci 2014 7;8:359. Epub 2014 Nov 7.

Department of Neurology, University of California San Francisco San Francisco, CA, USA.

Clinical data continue to reveal that the incidence of perinatal stroke is high, similar to that in the elderly. Perinatal stroke leads to significant morbidity and severe long-term neurological and cognitive deficits, including cerebral palsy. Experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. Cerebral vasculature undergoes substantial structural and functional changes during early postnatal brain development. Thus, the state of the vasculature could affect susceptibility of the neonatal brain to cerebral ischemia. In this review, we discuss some of the most recent findings regarding the neurovascular responses of the immature brain to focal arterial stroke in relation to neuroinflammation. We also discuss a possible role of the neonatal blood-CSF barrier in modulating inflammation and the long-term effects of early neurovascular integrity after neonatal stroke on angiogenesis and neurogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2014.00359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224076PMC
November 2014

Stem cells for neonatal stroke- the future is here.

Front Cell Neurosci 2014 25;8:207. Epub 2014 Jul 25.

Departments of Pediatrics and Neurology, UCSF San Francisco, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2014.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110439PMC
August 2014

Mechanisms of perinatal arterial ischemic stroke.

J Cereb Blood Flow Metab 2014 Jun 26;34(6):921-32. Epub 2014 Mar 26.

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

The incidence of perinatal stroke is high, similar to that in the elderly, and produces a significant morbidity and severe long-term neurologic and cognitive deficits, including cerebral palsy, epilepsy, neuropsychological impairments, and behavioral disorders. Emerging clinical data and data from experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. These studies have revealed that, far from just being a smaller version of the adult brain, the neonatal brain is unique with a very particular and age-dependent responsiveness to hypoxia-ischemia and focal arterial stroke. In this review, we discuss fundamental clinical aspects of perinatal stroke as well as some of the most recent and relevant findings regarding the susceptibility of specific brain cell populations to injury, the dynamics and the mechanisms of neuronal cell death in injured neonates, the responses of neonatal blood-brain barrier to stroke in relation to systemic and local inflammation, and the long-term effects of stroke on angiogenesis and neurogenesis. Finally, we address translational strategies currently being considered for neonatal stroke as well as treatments that might effectively enhance repair later after injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jcbfm.2014.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050239PMC
June 2014

Acute and chronic vascular responses to experimental focal arterial stroke in the neonate rat.

Transl Stroke Res 2013 Apr;4(2):179-88

Neonatal Brain Disorders Center. Department of Neurology. University of California San Francisco, San Francisco, USA.

The presence of active developmental angiogenesis and vascular outgrowth in the postnatal brain may differentially affect vascular responses to stroke in newborns and adults, but very little is known about the dynamics of vascular injury and re-growth after stroke during the neonatal period. In this study we used a clinically relevant animal model of ischemic arterial stroke in neonate rats, a transient middle cerebral artery occlusion (MCAO) in postnatal day 7 (P7), to characterize the effects of injury on vascular density and angiogenesis from acute through the chronic phase. A marked vessel degeneration and suppressed endothelial cell proliferation occur in the ischemic regions early after neonatal stroke. In contrast to what has been described in adult animals, endothelial cell proliferation and vascular density are not increased in the peri-ischemic regions during the first week after MCAO in neonates. By two weeks after injury, endothelial cell proliferation is increased in the cortical peri-ischemic region but these changes are not accompanied by an increased vascular density. Suppressed angiogenesis in injured postnatal brain that we report may limit recovery after neonatal stroke. Thus, enhancement of angiogenesis after neonatal stroke may be a promising strategy for the long-term recovery of the affected newborns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12975-012-0214-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665524PMC
April 2013

Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke.

Stroke 2013 May 28;44(5):1426-32. Epub 2013 Mar 28.

Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.

Background And Purpose: Brain injury caused by stroke is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. Mesenchymal stem cells (MSC) have been shown to improve outcome after neonatal hypoxic-ischemic brain injury mainly by secretion of growth factors stimulating repair processes. We investigated whether MSC treatment improves recovery after neonatal stroke and whether MSC overexpressing brain-derived neurotrophic factor (MSC-BDNF) further enhances recovery.

Methods: We performed 1.5-hour transient middle cerebral artery occlusion in 10-day-old rats. Three days after reperfusion, pups with evidence of injury by diffusion-weighted MRI were treated intranasally with MSC, MSC-BDNF, or vehicle. To determine the effect of MSC treatment, brain damage, sensorimotor function, and cerebral cell proliferation were analyzed.

Results: Intranasal delivery of MSC- and MSC-BDNF significantly reduced infarct size and gray matter loss in comparison with vehicle-treated rats without any significant difference between MSC- and MSC-BDNF-treatment. Treatment with MSC-BDNF significantly reduced white matter loss with no significant difference between MSC- and MSC-BDNF-treatment. Motor deficits were also improved by MSC treatment when compared with vehicle-treated rats. MSC-BDNF-treatment resulted in an additional significant improvement of motor deficits 14 days after middle cerebral artery occlusion, but there was no significant difference between MSC or MSC-BDNF 28 days after middle cerebral artery occlusion. Furthermore, treatment with either MSC or MSC-BDNF induced long-lasting cell proliferation in the ischemic hemisphere.

Conclusions: Intranasal administration of MSC after neonatal stroke is a promising therapy for treatment of neonatal stroke. In this experimental paradigm, MSC- and BNDF-hypersecreting MSC are equally effective in reducing ischemic brain damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.111.000326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694433PMC
May 2013

Genetic deletion of CD36 enhances injury after acute neonatal stroke.

Ann Neurol 2012 Dec;72(6):961-70

Department of Neurology, University of California at San Francisco, San Francisco,CA 94158, USA.

Objective: The scavenger receptor CD36 is injurious in acute experimental focal stroke and neurodegenerative diseases in the adult. We investigated the effects of genetic deletion of CD36 (CD36ko) on acute injury, and oxidative and inflammatory signaling after neonatal stroke.

Methods: Postnatal day 9 CD36ko and wild-type (WT) mice were subjected to a transient middle cerebral artery occlusion (MCAO). Injury, phagocytosis of dying cells, and CD36 inflammatory signaling were determined.

Results: While the volume of tissue at risk by diffusion-weighted magnetic resonance imaging during MCAO was similar in neonatal CD36ko and WT mice, by 24 hours after reperfusion, injury was more severe in CD36ko and was associated with increased caspase-3 cleavage and reduced engulfment of neurons expressing cleaved caspase-3 by activated microglia. No significant superoxide generation was observed in activated microglia in injured WT, whereas increased superoxide production in vessels and nuclear factor (NF)-κB activation induced by MCAO were unaffected by lack of CD36. Lyn expression was higher in injured CD36ko, and cell type-specific patterns of Lyn expression were altered; Lyn was expressed in endothelial cells and microglia in WT but predominantly in dying neurons in CD36ko.

Interpretation: Lack of CD36 results in poorer short-term outcome from neonatal focal stroke due to lack of attenuation of NF-κB-mediated inflammation and diminished removal of apoptotic neuronal debris. Although inhibition of CD36 does not seem to be a good therapeutic target for protection after acute neonatal stroke, as it is after adult stroke, seeking better understanding of CD36 signaling in particular cell populations may reveal important therapeutic targets for neonatal stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.23727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539222PMC
December 2012

Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat.

J Neurosci 2012 Jul;32(28):9588-600

Department of Neurology, University of California San Francisco, San Francisco, California 94143-0633, USA.

The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked whether the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2-24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70 kDa dextran) and small (3 kDa dextran), gadolinium (III)-diethyltriaminepentaacetic acid tracers remained largely undisturbed 24 h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24 h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and matrix metalloproteinase-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin, and zonula occludens protein 1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of cytokine-induced neutrophil chemoattractant-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability, and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.5977-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539825PMC
July 2012

Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke.

J Neurosci 2011 Sep;31(36):12992-3001

Department of Neurology, University of California, San Francisco, San Francisco, California 94143-0663, USA.

Macrophages are viewed as amplifiers of ischemic brain injury, but the origin of injury-producing macrophages is poorly defined. The role of resident brain macrophages-microglial cells-in stroke remains controversial. To determine whether microglial cells exert injurious effects after neonatal focal stroke, we selectively depleted these cells with intracerebral injection of liposome-encapsulated clodronate before transient middle cerebral artery occlusion in postnatal day 7 rats. Phagocytosis of apoptotic neurons by activated microglia was poor in animals with unmanipulated microglia, and depletion of these cells did not increase the number of apoptotic neurons. Lack of microglia increased the brain levels of several cytokines and chemokines already elevated by ischemia-reperfusion, and also increased the severity and volume of injury, suggesting that microglial cells contribute to endogenous protection during the subacute injury phase. Then, to determine whether accumulation of reactive oxygen species in microglia adversely affects phagocytosis of dying neurons and contributes to injury, we delivered reduced glutathione (GSH) into microglia, again using liposomes. Remarkably, pharmacologically increased intracellular GSH concentrations in microglia induced superoxide accumulation in lipid rafts in these cells, further increased the brain levels of macrophage chemoattractants, and exacerbated injury. Together, these data show that microglia are part of the endogenous defense mechanisms and that, while antioxidants can protect the injured neonatal brain, high levels of reducing equivalents in activated microglia, GSH, trigger superoxide production, favor the reorganization of lipids, amplify local inflammation and exacerbate injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2102-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539822PMC
September 2011

Cerebrovascular disease in children: recent advances in diagnosis and management.

J Child Neurol 2011 Sep 21;26(9):1074-100. Epub 2011 Jul 21.

Department of Pediatrics, Medical College of Georgia, Augusta, Georgia 30912-3700, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073811413585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289387PMC
September 2011

Magnetic resonance imaging (MRI) as a translational tool for the study of neonatal stroke.

J Child Neurol 2011 Sep 13;26(9):1145-53. Epub 2011 Jun 13.

Department of Pediatrics, University of California, San Francisco, CA, USA.

More than half of neonatal stroke survivors have long-term sequelae, including seizures and neurological deficits. Although the immature brain has tremendous potential for recovery, mechanisms governing repair are essentially unexplored. We investigated whether magnetic resonance imaging (MRI) early or late after transient middle cerebral arterial occlusion in postnatal day (P) 10 rats can serve as an intermediate endpoint for long-term studies. Injured animals selected by diffusion-weighted MRI during middle cerebral arterial occlusion were scanned using T2-weighted MRI at P18 and P25 (injury volumes on MRI and histology were compared) or were subjected to contrast-enhanced MRI at P13 to characterize cerebral microcirculatory disturbances and blood-brain barrier leakage. Injury volume during middle cerebral artery occlusion did not predict histological outcome at 2 weeks. Major reductions in injury volume occurred by P18, with no further changes by P25 and correlated with histological injury. Cerebral perfusion was significantly reduced in the injured caudate but blood-brain barrier leakage was small. Therefore, conventional T2-weighted MRI performed during a subchronic injury phase predicts a long-term histological outcome after experimental neonatal focal stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073811408308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695703PMC
September 2011

Cerebellar abnormalities following hypoxia alone compared to hypoxic-ischemic forebrain injury in the developing rat brain.

Neurobiol Dis 2011 Jan 16;41(1):138-46. Epub 2010 Sep 16.

Department of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA.

Two-day-old (P2) rat pups were subjected to either a global hypoxia or to electrocoagulation of the right carotid artery followed by 2.5 h hypoxia. Cellular and regional injury in the cerebellum (CB) was studied at 1, 2 and 19 days using immunohistology. Following hypoxia and hypoxia-ischemia, all neuronal populations of the CB were damaged in a subset of Purkinje cells. The decrease in the number of interneurons, as well as the thickness of molecular and granular layers was significant following hypoxia. Diffuse white matter damage, with loss of preoligodendrocytes was more severe following hypoxia than hypoxia-ischemia. Global hypoxia in the rat at P2 produces extensive damage to many cell types in different areas of the CB. The addition of unilateral forebrain ischemia does not increase the severity of these changes. Our data provide insight into the mechanisms of the changes observed in the CB of premature newborns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2010.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910430PMC
January 2011