repetitive neonatal erythropoietin and melatonin combinatorial treatment provides sustained repair of functional deficits in a rat model of cerebral palsy

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ID: 191450
2018
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Abstract
Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and results from perinatal brain injury (PBI). To test novel therapeutics to mitigate deficits from PBI, we developed a rat model of extreme preterm birth (<28 weeks of gestation) that mimics dual intrauterine injury from placental underperfusion and chorioamnionitis. We hypothesized that a sustained postnatal treatment regimen that combines the endogenous neuroreparative agents erythropoietin (EPO) and melatonin (MLT) would mitigate molecular, sensorimotor, and cognitive abnormalities in adults rats following prenatal injury. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague–Dawley rats. Uterine artery occlusion was performed for 60 min to induce placental insufficiency via transient systemic hypoxia-ischemia, followed by intra-amniotic injections of lipopolysaccharide, and laparotomy closure. On postnatal day 1 (P1), approximately equivalent to 30 weeks of gestation, injured rats were randomized to an extended EPO + MLT treatment regimen, or vehicle (sterile saline) from P1 to P10. Behavioral assays were performed along an extended developmental time course (n = 6–29). Open field testing shows injured rats exhibit hypermobility and disinhibition and that combined neonatal EPO + MLT treatment repairs disinhibition in injured rats, while EPO alone does not. Furthermore, EPO + MLT normalizes hindlimb deficits, including reduced paw area and paw pressure at peak stance, and elevated percent shared stance after prenatal injury. Injured rats had fewer social interactions than shams, and EPO + MLT normalized social drive. Touchscreen operant chamber testing of visual discrimination and reversal shows that EPO + MLT at least partially normalizes theses complex cognitive tasks. Together, these data indicate EPO + MLT can potentially repair multiple sensorimotor, cognitive, and behavioral realms following PBI, using highly translatable and sophisticated developmental testing platforms.
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jantzie2018frontiersrepetitive Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Lauren L. Jantzie;Lauren L. Jantzie;Akosua Y. Oppong;Fatu S. Conteh;Tracylyn R. Yellowhair;Joshua Kim;Gabrielle Fink;Adam R. Wolin;Frances J. Northington;Shenandoah Robinson
Journal journal of photochemistry and photobiology a: chemistry
Year 2018
DOI
10.3389/fneur.2018.00233
URL
http://journal.frontiersin.org/article/10.3389/fneur.2018.00233/full
Keywords
inflammation social interaction chorioamnionitis cerebral palsy diseases of the nervous system

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