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.
Highlights
Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and typically results from perinatal brain injury (PBI) [1, 2]
Prenatal injury had a significant effect on disinhibition, with sham rats exploring the peripheral zone for significantly longer periods compared to vehicle-treated injury rats (p = 0.001; Figure 1C), and spending less time in the neutral zone (p = 0.041; Figure 1D)
Further analyses of the maladaptive learning in the reversal paradigm consistent with a lack of cognitive flexibility, indicated a trend for improved performance during both perseveration and learning phases of the reversal paradigm. These results show that touchscreen testing can be used in PBI to distinguish complex behavior related to executive function and learning and that EPO + MLT can at least partially reverse the reduced cognition present after prenatal injury
Summary
Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and typically results from perinatal brain injury (PBI) [1, 2]. While preterm birth is a common etiologic antecedent, motor impairment and associated deficits can arise from other insults to the developing central nervous system (CNS), including trauma and stroke. The scope of PBI has shifted over recent decades as more preterm infants survive [3,4,5], and the proportion of children with more severe motor impairment has increased in the USA [6]. Within subpopulations of neonates with PBI, multiple injury mechanisms have been implicated, and emerging evidence strongly suggests that each newborn suffers a unique vulnerability to CNS injury from a combination of [1] inflammation from prenatal infection and/or hypoxia-ischemia (HI); [2] individualized risk from genetic and/ or congenital predisposition and acquired prenatal exposures to drugs, toxins, and nutritional status; and [3] postnatal stresses, such as sepsis and surgery. There is an urgent need for safe, effective interventions for PBI, and subsequent CP and related deficits
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