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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-017-0539-1) contains supplementary material, which is available to authorized users.

Rh-IFN-α attenuates neuroinflammation and improves neurological function by inhibiting NF-κB through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model

“…(Lekic T et al, 2015). GMH is a devastating neonatal stroke characterized as neuroinflammation, hydrocephalus, primary and secondary brain injury, neurodevelopmental delay (Agyemang et al, 2017). Furthermore, neuroinflammation is also a trigger of secondary injury after GMH.…”

Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups

“…These morphological changes were most prominent at P0 and P2, coinciding in time with the finding of decreased EGL proliferation. The vulnerability of Purkinje cell development to insults associated with preterm birth have been recently shown in rat pups exposed to neonatal hyperoxia and also in preterm rabbit pups with preterm cerebral intraventricular hemorrhage exhibiting delayed maturation of Purkinje cells and decreased granular precursor cell proliferation [26, 27]. The cerebellar Purkinje cells have several key functions relating to EGL proliferation, and subsequent inward cell migration and Purkinje cell secretion of the transcription factor Shh are key for EGL precursor cell proliferation [12, 13, 28].…”

The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions

“…In a preterm rabbit pup model of IVH, it has been observed that extracellular Hb and its downstream metabolites cause structural damage of the choroid plexus [ 84 , 85 , 86 ]. Furthermore, following IVH, extracellular Hb was found to be widely distributed in periventricular white matter and deposited in remote regions of the cerebellar white matter, leading to alteration of normal development of the cerebellar cortex [ 81 , 87 ].…”