Cerebral intraventricular hemorrhage and post-hemorrhagic ventricular dilatation in preterm infants: new mechanistic insights and potential treatment strategies

Sammanfattning: Intraventricular hemorrhage (IVH) is one of the major co-morbidities of premature birth associated with post-hemorrhagic ventricular dilatation (PHVD) development, long-term neurodevelopmental impairment, behavioral problems, special educational needs, and dependency on social security.Hypothesis and aims: We believe that extravasated blood and further release of extracellular hemoglobin (Hb) are crucial in brain injury following IVH and consequent development of PHVD. The overall goal of this project focuses on further pathogenetic insights of white and gray matter (GM) injury following IVH and the development of possible neuroprotective treatment strategies that may promote brain development in preterm infants.Methods: Paper I. We characterized extracellular Hb distribution within preriventricular white matter (WM) in preterm rabbit pups following IVH. Paper II. We evaluated the cerebral biodistribution and possible functional neuroprotection of intracerebroventricularly administered alpha-1-microglobulin (A1M), a heme and free radical scavenger, in preterm rabbit pups following IVH. Paper III. We conducted a comprehensive review of preclinical and clinical studies on WM injury following IVH. Paper IV. We evaluated high-frequency ultrasound (HFU) as a tool for the reconstruction of volumetric volume in preterm rabbit pups with PHVD and compared its accuracy and reliability with that of a gold-standard – magnetic resonance imaging (MRI). Paper V. We established a novel model of PHVD in preterm rabbit pups and characterized the survival, neurobehavior, WM, and GM injury, as well as altered corticogenesis.Results: Paper I. Following IVH extracellular Hb was widely distributed throughout the brain WM, particularly in periventricular white matter areas with high extracellular plasticity following IVH. Paper II. Exogenous A1M (recombinant) was extensively distributed within brain WM with further extension into cerebellar WM following IVH. Moreover, A1M exhibited high co-existence with extracellular Hb. Administration of A1M (human) decreased pro-inflammatory and oxidative damage. Paper III. A wide range of animal models have been used to explore pathogenetic mechanisms of IVH and related brain damage; possible targets involved in enhancing brain damage have been identified. Nevertheless, the effectiveness of potential interventions is still limited. Paper IV. HFU-based volumetric reconstruction of brain ventricles is highly accurate and reliable as compared to MRI and may be a promising bed-side tool for evaluating of progression of PHVD in preterm infants. Paper V. IVH and PHVD lead to a long-term alteration of cortical myelination microstructure, disruption of cortical organization, selectively reduction in neurogenesis and synaptogenesis, reduction in parvalbumin-positive interneurons and their dysmaturation.Conclusions: Extracellular Hb travels easily throughout brain WM following IVH and it may be one of the key factors for induction of brain damage by triggering pro-inflammatory and oxidative cascades. Furthermore, IVH, leading to PHVD, disrupts normal corticogenesis, alters myelin microstructure, causes a selective reduction in neurons, interneurons, and synapses. A1M, as a heme and free radicals scavenger, may attenuate WM damage, confirming that extracellular Hb is causative in ongoing neuroinflammation following IVH. Thus, A1M may be a possible treatment strategy in preterm infants with IVH. HFU represents a highly accurate tool for volumetric reconstruction of ventricles for diagnosis and management of PHVD.