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Cerebellar Exposure to Cell-Free Hemoglobin Following Preterm Intraventricular Hemorrhage: Causal in Cerebellar Damage?

Journal article
Authors A. A. Agyemang
K. Sveinsdottir
S. Vallius
S. Sveinsdottir
M. Bruschettini
O. Romantsik
Ann Hellström
L. E. H. Smith
L. Ohlsson
B. Holmqvist
M. Gram
D. Ley
Published in Translational Stroke Research
Volume 8
Issue 5
Pages 461-473
ISSN 1868-4483
Publication year 2017
Published at Institute of Neuroscience and Physiology
Pages 461-473
Language en
Keywords Intraventricular hemorrhage, Hemoglobin, Haptoglobin, Cerebellum, External granular layer, germinal matrix hemorrhage, extracellular hemoglobin, brain-injury, intracerebral hemorrhage, subarachnoid hemorrhage, mechanisms, infants, disease, growth, iron
Subject categories Neurosciences


Decreased cerebellar volume is associated with intraventricular hemorrhage (IVH) in very preterm infants and may be a principal component in neurodevelopmental impairment. Cerebellar deposition of blood products from the subarachnoid space has been suggested as a causal mechanism in cerebellar underdevelopment following IVH. Using the preterm rabbit pup IVH model, we evaluated the effects of IVH induced at E29 (3 days prior to term) on cerebellar development at term-equivalent postnatal day 0 (P0), term-equivalent postnatal day 2 (P2), and term-equivalent postnatal day 5 (P5). Furthermore, the presence of cell-free hemoglobin (Hb) in cerebellar tissue was characterized, and cell-free Hb was evaluated as a causal factor in the development of cerebellar damage following preterm IVH. IVH was associated with a decreased proliferative (Ki67-positive) portion of the external granular layer (EGL), delayed Purkinje cell maturation, and activated microglia in the cerebellar white matter. In pups with IVH, immunolabeling of the cerebellum at P0 demonstrated a widespread presence of cell-free Hb, primarily distributed in the white matter and the molecular layer. Intraventricular injection of the Hb scavenger haptoglobin (Hp) resulted in a corresponding distribution of immunolabeled Hp in the cerebellum and a partial reversal of the damaging effects observed following IVH. The results suggest that cell-free Hb is causally involved in cerebellar damage following IVH and that blocking cell-free Hb may have protective effects.

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