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Preterm intraventricular cerebral hemorrhage: role of cell-free hemoglobin

Agyemang, Alex Adusei LU (2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(22).
Abstract
Cerebral intraventricular hemorrhage in preterm infants continues to be a major clinical problem associated with neurodevelopmental abnormalities manifested by cognitive, behavioral, attentional, social and motor deficits.
Hypothesis and aims: The central thesis is that the cytotoxicity of extravasated blood and of consequently released cell-free hemoglobin(Hb) is pivotal for the pathophysiological events causally involved in brain injury. The general aim focuses on the development and implementation of novel neuroprotective strategies with the aim of promoting brain development in preterm infants with high risk for neurodevelopmental impairment.
Methods: Paper I. The presence and distribution of cell-free Hb in the... (More)
Cerebral intraventricular hemorrhage in preterm infants continues to be a major clinical problem associated with neurodevelopmental abnormalities manifested by cognitive, behavioral, attentional, social and motor deficits.
Hypothesis and aims: The central thesis is that the cytotoxicity of extravasated blood and of consequently released cell-free hemoglobin(Hb) is pivotal for the pathophysiological events causally involved in brain injury. The general aim focuses on the development and implementation of novel neuroprotective strategies with the aim of promoting brain development in preterm infants with high risk for neurodevelopmental impairment.
Methods: Paper I. The presence and distribution of cell-free Hb in the periventricular white matter was evaluated in preterm rabbit pups with intraventricular hemorrhage(IVH). Paper II. The distribution, deposition and effect of cell-free Hb on cerebellar development was investigated following IVH in preterm rabbit pups. The protective effect of the cell-free Hb scavenger haptoglobin (Hp) was evaluated. Paper III. The relative cytotoxicity of the different cell-free Hb metabolites was evaluated in mixed glial cell culture. Paper IV. The biodistribution and functional protection of intraventricularly administered recombinant ( alpha 1 microglobulin (rA1M), a heme and radical scavenger was investigated following IVH in preterm rabbit pups.
Results: Paper I. IVH was associated with extensive amounts of cell-free Hb in the periventricular white matter, with a wide distribution throughout the brain. Paper II. IVH was followed by a decreased proliferation in the external granular layer (EGL), delayed Purkinje cell maturation and activated microglia in the cerebellum. Cell-free Hb was present in all cerebellar layers, with a gradient towards the molecular and white matter layers. Intraventricular administration of Hp resulted in a partial reversion of the damaging effects following IVH. Paper III. Met/oxidized Hb and not oxyHb was found to initiate a proinflammatory and oxidative response with cytoskeletal disintegration in mixed glial cell cultures. Paper IV. Administered rA1M following IVH was widely distributed in periventricular white matter tissue and present throughout the fore- and mid brain extending to the cerebellum,with a high coexistence of cell-free Hb. Administration of r A1M resulted in an attenuation of proinflammatory and oxidative damage.
Conclusions: IVH is characterized by the penetration of cell-free Hb into periventricular brain tissue and cerebellum resulting in a proinflammatory and oxidative damage to the brain. Hp and A1M, scavengers of cell-free Hb and Hb
metabolites respectively, attenuate the damage sustained by the periventricular white matter and cerebellum, affirming cell-free Hb to be causally involved in the brain damage resulting from IVH. Hp and A1M hence appear potential candidates for neuroprotective strategies against brain damage following IVH
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author
supervisor
opponent
  • Professor Ballabh, Praveen, Albert Einstein College, New York
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Intraventricular hemorrhage, Preterm birth, Haptoglobin, Alpha 1 microglobulin, cerebellar hypoplasia, periventricular white matter, cell-free hemoglobin
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2019
issue
22
pages
59 pages
publisher
Lund University: Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
defense date
2019-03-15 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-751-6
language
English
LU publication?
yes
id
0a7fac93-64e3-4aa1-a774-264fde2837f7
date added to LUP
2019-02-20 16:49:58
date last changed
2019-11-19 13:49:46
@phdthesis{0a7fac93-64e3-4aa1-a774-264fde2837f7,
  abstract     = {Cerebral intraventricular hemorrhage in preterm infants continues to be a major clinical problem associated with   neurodevelopmental abnormalities manifested by cognitive, behavioral, attentional, social and motor deficits.  <br/>Hypothesis and aims: The central thesis is that the cytotoxicity of extravasated blood and of consequently released cell-free hemoglobin(Hb) is pivotal for the pathophysiological events causally involved in brain injury. The general aim focuses on the development and implementation of novel neuroprotective strategies with the aim of promoting brain development in preterm infants with high risk for neurodevelopmental impairment.<br/>Methods: Paper I.  The presence and distribution of cell-free Hb in the periventricular white matter was evaluated in preterm rabbit pups with intraventricular hemorrhage(IVH). Paper II. The distribution, deposition and effect of cell-free Hb on cerebellar development was investigated following IVH in preterm rabbit pups. The protective effect of the cell-free Hb scavenger haptoglobin (Hp) was evaluated. Paper III. The relative cytotoxicity of the different cell-free Hb metabolites was evaluated in mixed glial cell culture. Paper IV.  The biodistribution and functional protection of intraventricularly administered  recombinant ( alpha 1 microglobulin (rA1M), a heme and radical scavenger  was investigated following IVH in preterm rabbit pups.<br/>Results: Paper I. IVH was associated with extensive amounts of cell-free Hb in the periventricular white matter, with a wide distribution throughout the brain. Paper II. IVH was followed by a decreased proliferation in the external granular layer (EGL), delayed Purkinje cell maturation and activated microglia in the cerebellum. Cell-free Hb was present in all cerebellar layers, with a gradient towards the molecular and white matter layers. Intraventricular administration of Hp resulted in a partial reversion of the damaging effects following IVH. Paper III. Met/oxidized Hb and not oxyHb was found to initiate a proinflammatory and oxidative response  with cytoskeletal disintegration in mixed glial cell cultures. Paper IV. Administered rA1M following IVH was widely distributed in  periventricular white matter tissue and present throughout the fore- and mid brain extending to the cerebellum,with a  high coexistence of cell-free Hb. Administration of r A1M resulted in an attenuation of proinflammatory and oxidative damage.<br/>Conclusions: IVH is characterized by the penetration of cell-free Hb into periventricular brain tissue and cerebellum resulting in a proinflammatory and oxidative damage to the brain. Hp and A1M, scavengers of cell-free Hb and Hb<br/>metabolites respectively, attenuate the damage sustained by the periventricular white matter and cerebellum, affirming cell-free Hb  to be causally involved in the brain damage resulting from IVH. Hp and A1M hence appear potential candidates for neuroprotective strategies against brain damage following IVH<br/>},
  author       = {Agyemang, Alex Adusei},
  isbn         = {978-91-7619-751-6},
  issn         = {1652-8220},
  language     = {eng},
  number       = {22},
  publisher    = {Lund University: Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Preterm intraventricular cerebral hemorrhage: role of cell-free hemoglobin},
  url          = {https://lup.lub.lu.se/search/ws/files/60624322/e_nailing_ex_Felix.pdf},
  volume       = {2019},
  year         = {2019},
}