title: Effects of inter-alpha inhibitor proteins on neonatal brain injury: Age, task and treatment dependent neurobehavioral outcomes.
abstract: Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full term birth related complications. HI injury often results in learning and processing deficits that reflect widespread damage to an extensive range of cortical and sub-cortical brain structures. Further, inflammation has been implicated in the long-term progression and severity of HI injury. Recently, inter-alpha inhibitor proteins (IAIPs) have been shown to attenuate inflammation in models of systemic infection. Importantly, preclinical studies of neonatal HI injury and neuroprotection often focus on single time windows of assessment or single behavioral domains. This approach limits translational validity, given evidence for a diverse spectrum of neurobehavioral deficits that may change across developmental windows following neonatal brain injury. Therefore, the aims of this research were to assess the effects of human IAIPs on early neocortical cell death (72h post-insult), adult regional brain volume measurements (cerebral cortex, hippocampus, striatum, corpus callosum) and long-term behavioral outcomes in juvenile (P38-50) and adult (P80+) periods across two independent learning domains (spatial and non-spatial learning), after postnatal day 7 HI injury in rats. Here, for the first time, we show that IAIPs reduce acute neocortical neuronal cell death and improve brain weight outcome 72h following HI injury in the neonatal rat. Further, these longitudinal studies are the first to show age, task and treatment dependent improvements in behavioral outcome for both spatial and non-spatial learning following systemic administration of IAIPs in neonatal HI injured rats. Finally, results also show sparing of brain regions critical for spatial and non-spatial learning in adult animals treated with IAIPs at the time of injury onset. These data support the proposal that inter-alpha inhibitor proteins may serve as novel therapeutics for brain injury associated with premature birth and/or neonatal brain injury and highlight the importance of assessing multiple ages, brain regions and behavioral domains when investigating experimental treatment efficacy.
authors.affiliation: Department of Psychology, Rhode Island College, 600 Mount Pleasant Ave., Providence, RI 02904, USA. Electronic address: Sthrelkeld@ric.edu.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Threlkeld
authors.affiliation: Department of Psychology, Rhode Island College, 600 Mount Pleasant Ave., Providence, RI 02904, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Gaudet
authors.affiliation: Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA.
authors.forename: Molly E
authors.initials: ME
authors.lastname: La Rue
authors.affiliation: Department of Psychology, Rhode Island College, 600 Mount Pleasant Ave., Providence, RI 02904, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Dugas
authors.affiliation: Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Hill
authors.affiliation: ProThera Biologics, Inc., East Providence, RI 02914, USA.
authors.forename: Yow-Pin
authors.initials: YP
authors.lastname: Lim
authors.affiliation: Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Stonestreet
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000510:Alpha-Globulins / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000510:Alpha-Globulins; C011877:inter-alpha-inhibitor
keywords: Brain volume estimation; Neonatal brain injury; Neuronal cell death; Rodent model; Spatial and non-spatial learning; Water maze
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