Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy

Abstract

OBJECTIVE-To determine whether maternal intrauterine endotoxin administration leads to neurobehavioral deficits in newborn rabbits. STUDY DESIGN-PregnantNew Zealand white rabbits were injected with 1ml saline (n=8) or 20μg/kg of lipolysaccharide in saline (LPS) (n=8) into the uterine wall on day 28/31 of gestation. On postnatal day 1, kits [saline (n=30) and LPS (n=18) from 4 consecutive litters] underwent neurobehavioral testing. Neonatal brains were stained for microglial cells and myelin.RESULTS-LPS-group kits were hypertonic and demonstrated significant impairment in posture, righting reflex, locomotion and feeding, along with neuroinflammation indicated by activated microglia, and hypomyelination in the periventricular regions. A greater mortality was noted in the LPS group (16 stillbirths from 3 litters vs. 3 from 1 litter).CONCLUSION-Maternal intrauterine endotoxin administration leads to white matter injury and motor deficits in the newborn rabbit resulting in a phenotype that resembles those found in periventricular leukomalacia and cerebral palsy.

Decreased Cortical Serotonin in Neonatal Rabbits Exposed to Endotoxin in Utero

“…All kits were born spontaneously on gestational day 31 and the litter size ranged from 7 to 11 kits. Kits born to dams exposed to endotoxin in utero were born with motor deficits suggestive of cerebral palsy as previously described (Saadani-Makki et al, 2008).…”

A New Rabbit Model of Pediatric Traumatic Brain Injury

“…6A). Cognitive deficits did not differ significantly between the male (n = 6) and female (n = 10) kits in the TBI group (male, 33.3 -10.5%; female, 36.7 -13.2%; t (14) = 0.5; p = 0.6). In addition, TBI kits (n = 12) spent significantly less time exploring the novel object than did the naïve (n = 11) and sham (n = 8) kits ( p < 0.001; Fig.…”

“…This is 1.4 times greater than in the rabbit model but resulted in a lesion volume of only *10% at 7 d post-injury in the rat, which is a third of the lesion volume seen in the rabbit. 43 Compared with rodents, the white matter development of rabbits and microglial presence and distribution in the brain is closer to that in humans, 14 which may increase the vulnerability of the developing rabbit brain, resulting in a more severe secondary injury as seen clinically.…”

“…32,33 Microglial presence in the white matter tracts parallels that of oligodendrocyte maturation and peak myelination, extending from before birth to the postnatal period, similar to that seen in humans. 14,15 In humans, myelination of sensory and motor fibers starts at birth and continues during the first year of life, 34,35 with persistence of microglia in the white matter tracts up to two years of age, which corresponds to the period of peak myelination. 36 Therefore, the microglial response seen after injury in relation to development would mimic that seen in humans.…”

“…Although it is very difficult to have an animal model where all developmental processes mimic that in humans, the rabbit model is unique because white matter development, microglial presence in the white matter tracts, and the pattern of brain growth parallels that in humans. 14,15 In this study, we have developed a new rabbit model of pediatric TBI of focal contusion that results in neurologic responses and histologic changes similar to that seen in children, which would enable evaluation of novel therapies for treatment of TBI.…”