Perinatal brain injury resulting in neurodevelopmental delay (ND), cerebral palsy (CP) and seizures represents the one of most severe disabilities in childhood. The incidence of CP is 40-148 in preterm and 1-2/1,000 in full term infants. Developmental disabilities place a huge burden on society (lifetime costs per person: ~1 million dollars), emphasizing the urgent need for improved treatment strategies to reduce perinatal brain damage. Unfortunately, hypothermia is the only approved therapy for brain damage in infants and is only partially protective. It can only be used to treat hypoxic-ischemic (HI) encephalopathy in full term infants, and cannot be used in preterm infants in whom supportive care is the only `therapy' to attenuate brain damage. Cytokines represent a final common pathway, which cause/augment fetal/neonatal brain damage. Inter-alpha inhibitor proteins (IAIPs) down-regulate pro-inflammatory cytokines in sepsis and inhibit destructive serine proteases. Little information is available about IAIPs in brain. Recent data suggests that bikunin, a fragment of IAIPs, isolated from urine, attenuates stroke-related brain injury and experimental autoimmune encephalomyelitis-related white matter loss in adult rats. However, the half-life of bikunin is very short (3-10 min), compared with the complexed form isolated from blood (18 h in neonatal rats), requiring large quantities of protein and continuous intravenous infusions. The potential neuroprotective effects of IAIPs isolated from blood have not been examined except for our recent data. We will examine the neuroprotective effects of the blood-derived IAIPs. We anticipate that this form will be a more viable neuroprotective agent for clinical use. Our preliminary studies with blood-derived IAIPs suggest that this agent has remarkable neuroprotective effects in HI neonatal rats and fetal sheep after ischemic injury. Our overall goal is to develop a novel effective therapy to treat ischemic brain damage using the preclinical fetal sheep model in which IAIPs can be given by the clinically relevant intravenous route. We hypothesize that systemic IAIPs administration attenuates the development of ischemic-reperfusion related injury in the immature brain. The purpose of this proposal is to provide a strong biological basis to support the use of IAIPs as therapeutic agents to treat ischemia-related brain injury in the immature brain.
The aims are: (1) To establish the dose of IAIPs with the greatest neuroprotective efficacy in the fetus; (2) To examine the neuroprotective efficacy of delayed treatment with IAIPs on brain injury; (3) To determine the pharmacokinetics of intravenously administered IAIPs in the ovine fetus. Fetuses will be surgically prepared; brain ischemia induced by carotid occlusion and injury measured by a multidisciplinary approach using ECoG, physiological, biochemical, pathological, immunological, immunohistochemical, and molecular methods. Results of the studies could yield novel information that will accelerate the use of IAIPs as neuroprotective agents to treat brain injury in the fetus/neonate potentially t prevent ND and CP in infants.
Perinatal brain injury often results in severe developmental disabilities such as neurodevelopmental delay and cerebral palsy. Consequently, they place a huge burden on society, emphasizing the paramount need for improved treatment strategies to reduce individual and societal burdens related to perinatal brain damage. Very limited information exists regarding the neuroprotective properties of Inter-alpha inhibitor proteins (IAIPs). We have generated preliminary data suggesting a blood-derived long-acting form of IAIPs has remarkable neuroprotective properties in a neonatal rodent model of hypoxia-ischemia and fetal sheep after ischemia-reperfusion related injury. The findings we will obtain in the proposed studies could be translated into an important novel treatment strategy for human full-term and/or premature infants exposed to hypoxic-ischemic brain injury, as a form of IAIPs, bikunin, isolated from urine is already in clinical use to treat acute pancreatitis and other inflammatory disorders in Japan and China. Thus, the studies described in this proposal have exciting translational potential to prevent or attenuate brain injury in infants at risk for brain damage, mental retardation, and/or cerebral palsy.
| Mandelbaum, David E; Arsenault, Amanda; Stonestreet, Barbara S et al. (2018) Neuroinflammation-Related Encephalopathy in an Infant Born Preterm Following Exposure to Maternal Diabetic Ketoacidosis. J Pediatr 197:286-291.e2 |
| Htwe, Soe Soe; Wake, Hidenori; Liu, Keyue et al. (2018) Inter-? inhibitor proteins maintain neutrophils in a resting state by regulating shape and reducing ROS production. Blood Adv 2:1923-1934 |
| Disdier, Clémence; Zhang, Jiyong; Fukunaga, Yuki et al. (2018) Alterations in inter-alpha inhibitor protein expression after hypoxic-ischemic brain injury in neonatal rats. Int J Dev Neurosci 65:54-60 |
| Spasova, Mariya S; Chen, Xiaodi; Sadowska, Grazyna B et al. (2017) Ischemia reduces inter-alpha inhibitor proteins in the brain of the ovine fetus. Dev Neurobiol 77:726-737 |
| Spasova, Mariya S; Sadowska, Grazyna B; Threlkeld, Steven W et al. (2014) Ontogeny of inter-alpha inhibitor proteins in ovine brain and somatic tissues. Exp Biol Med (Maywood) 239:724-36 |
