Model of Cerebral Palsy in the Perinatal Rabbit

Tan, Sidhartha; Drobyshevsky, Alexander; Jilling, Tamás; Ji, Xinhai; Ullman, Lauren Marie; Englof, Ila; Derrick, Matthew

doi:10.1177/08830738050200120801

Cited by 54 publications

(65 citation statements)

References 27 publications

(35 reference statements)

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“…[76][77][78][79][80] Many of the animal studies reviewed here have been based on the Vannucci model in rodents. This model involves unilateral carotid artery ligation followed by a period of moderate hypoxia in neonatal rats or mice.…”

Section: Animal Models Of Human Cb Transplantation For Hiementioning

confidence: 99%

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Liao

Cotten

Tan

et al. 2012

Bone Marrow Transplant

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Brain injury resulting from perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality in infants and chronic neurologic disability in surviving children. Recent multicenter clinical trials demonstrated the effectiveness of hypothermia initiated within the first 6 postnatal hours to reduce the risk of death or major neurological disabilities among neonates with HIE. However, in these trials, approximately 40% of cooled infants died or survived with significant impairments. Therefore, adjunct therapies are required to improve the outcome in neonates with HIE. Cord blood (CB) is a rich source of stem cells. Administration of human CB cells in animal models of HIE has generally resulted in improved outcomes and multiple mechanisms have been suggested including anti-inflammation, release of neurotrophic factors and stimulation of endogenous neurogenesis. Investigators at Duke are conducting studies of autologous CB infusion in neonates with HIE and in children with cerebral palsy. These pilot studies indicate no added risk from the regimens used, but results of ongoing placebo-controlled trials are needed to assess efficacy. Meanwhile, further investigations are warranted to determine the best strategies, that is, timing, dosing, route of delivery, choice of stem cells and ex vivo modulations, to attain long-term benefits of CB stem cell therapy.

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Section: Animal Models Of Human Cb Transplantation For Hiementioning

confidence: 99%

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Liao

Cotten

Tan

et al. 2012

Bone Marrow Transplant

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“…8,9 Briefly, in vivo uterine ischemia was induced in pregnant dams (Myrtle's Rabbits; Thompson Station, TN) by inflation of an aortic balloon at a level…”

Section: Methodsmentioning

confidence: 99%

“…8,9 Briefly, in vivo uterine ischemia was induced in pregnant dams (Myrtle's Rabbits; Thompson Station, TN) by inflation of an aortic balloon at a level proximal to the uterine arteries. 8,10 -12 This protocol resulted in global hypoxia to the fetus that was accompanied by immediate fetal bradycardia (from 180 to 80 bpm) and an immediate decrease in microvascular blood flow (laser Doppler measurements) to the fetal cerebral cortex which remained down for the duration of uterine ischemia.…”

Section: Methodsmentioning

confidence: 99%

“…8,9 Newborn kits that survived (58%) the hypoxicischemic insult, at 22 days' gestation (E22), displayed significant impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. 8,9 Increased tone of the limbs at rest and with active flexion and extension were observed in the survivors of the preterm ( Figure 1A and 1B) but not in the survivors of the near-term insult.…”

Section: Cerebral Palsy Model In Rabbitsmentioning

confidence: 99%

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A Model of Cerebral Palsy From Fetal Hypoxia-Ischemia

Derrick

Drobyshevsky

et al. 2007

Stroke

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Abstract-Disorders of the maternal-placental-fetal unit often results in fetal brain injury, which in turn results in one of the highest burdens of disease, because of the lifelong consequences and cost to society. Investigating hypoxia-ischemia in the perinatal period requires the factoring of timing of the insult, determination of end-points, taking into account the innate development, plasticity, and enhanced recovery. Prenatal hypoxia-ischemia is believed to account for a majority of cerebral palsy cases. We have modeled sustained and repetitive hypoxia-ischemia in the pregnant rabbit in utero to mimic the insults of abruptio placenta and labor, respectively. Rabbits have many advantages over other animal species; principally, their motor development is in the perinatal period, akin to humans. Sustained hypoxia-ischemia at 70% (E22) and 79% (E25) caused stillbirths and multiple deficits in the postnatal survivors. The deficits included impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. Hypertonia was observed in the E22 and E25 survivors and persisted for at least 11 days. Noninvasive imaging using MRI suggests that white matter injury in the internal capsule could explain some of the hypertonia. Further investigation is underway in other vulnerable regions such as the basal ganglia, thalamus and brain stem, and development of other noninvasive determinants of motor deficits. erebral palsy is a nonprogressive disorder of the developing brain principally affecting the motor system. Cerebral palsy affects 2 to 3 per 1000 newborns, with a conservative estimate of its impact on society being Ϸ$5 billion per year. Cerebral palsy can be associated with epilepsy and abnormalities of speech, vision, and intellect. The impact of diseases affecting the newborn are much higher than diseases that affect the elderly because of the burden of disease when one considers mortality, years of life lost, and years of productive life lost. If one compares the economic impact of disease of an elderly person at the end of life compared with that of disease of a fetus or baby, the impact of the latter is far more. Lifetime costs for all persons of cerebral palsy are estimated to total $11.5 billion. 1 These costs underscore the need to urgently develop preventive and secondary therapeutic measures for the fetus and newborn. Little progress has been made over the past few decades on the prevalence of cerebral palsy. [2][3][4] The lack of development of new therapies has been partly because of the malpractice climate in United States. 5 Progress is also slow because of the unique obstacles facing investigators studying brain injury in the perinatal period, principally related to the issue of timing. 6 During the progression of neurological development, the timing of the insult and of end points becomes crucial in any study. The investigator has to take into account not only the plasticity of the stage of development but also th...

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“…15,37 Thus, an injury at this time will enable us to evaluate the effect of the injury on microglial activation and white matter development. Moreover, at this time-point, the major cortical layers in the rabbits are already formed, but cortical development (e.g., visual and auditory) is not completed.…”

Section: Rationale For Timing Of Injury and Outcome Evaluationmentioning

confidence: 99%

A New Rabbit Model of Pediatric Traumatic Brain Injury

Zhi

Saraswati

Koehler

et al. 2015

Journal of Neurotrauma

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Traumatic brain injury (TBI) is a common cause of disability in childhood, resulting in numerous physical, behavioral, and cognitive sequelae, which can influence development through the lifespan. The mechanisms by which TBI influences normal development and maturation remain largely unknown. Pediatric rodent models of TBI often do not demonstrate the spectrum of motor and cognitive deficits seen in patients. To address this problem, we developed a New Zealand white rabbit model of pediatric TBI that better mimics the neurological injury seen after TBI in children. On postnatal Day 5-7 (P5-7), rabbits were injured by a controlled cortical impact (6-mm impactor tip; 5.5 m/sec, 2-mm depth, 50-msec duration). Rabbits from the same litter served as naïve (no injury) and sham (craniotomy alone) controls. Functional abilities and activity levels were measured 1 and 5 d after injury. Maturation level was monitored daily. We performed cognitive tests during P14-24 and sacrificed the animals at 1, 3, 7, and 21 d after injury to evaluate lesion volume and microglia. TBI kits exhibited delayed achievement of normal developmental milestones. They also demonstrated significant cognitive deficits, with lower percentage of correct alternation rate in the T-maze (n = 9-15/group; p < 0.001) and less discrimination between novel and old objects ( p < 0.001). Lesion volume increased from 16% at Day 3 to 30% at Day 7 after injury, indicating ongoing secondary injury. Activated microglia were noted at the injury site and also in white matter regions of the ipsilateral and contralateral hemispheres. The neurologic and histologic changes in this model are comparable to those reported clinically. Thus, this rabbit model provides a novel platform for evaluating neuroprotective therapies in pediatric TBI.

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Model of Cerebral Palsy in the Perinatal Rabbit

Cited by 54 publications

References 27 publications

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

A Model of Cerebral Palsy From Fetal Hypoxia-Ischemia

A New Rabbit Model of Pediatric Traumatic Brain Injury

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