Tandem insults of prenatal ischemia plus postnatal raised intrathoracic pressure in a novel rat model of encephalopathy of prematurity

Laboratory investigation

Michael T. KoltzDepartments of Neurosurgery,

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 M.D.
,
Cigdem TosunDepartments of Neurosurgery,

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 B.S.
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David B. KurlandDepartments of Neurosurgery,

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 B.A.
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Turhan CoksayganPathology, and

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 D.V.M., Ph.D.
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Rudolph J. CastellaniPathology, and

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 M.D.
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Svetlana IvanovaDepartments of Neurosurgery,

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 Ph.D.
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Volodymyr GerzanichDepartments of Neurosurgery,

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 M.D., Ph.D.
, and
J. Marc SimardDepartments of Neurosurgery,
Pathology, and
Physiology, University of Maryland School of Medicine, Baltimore, Maryland

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 M.D., Ph.D.
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Encephalopathy of prematurity (EP) is common in preterm, low birth weight infants who require postnatal mechanical ventilation. The worst types of EP are the hemorrhagic forms, including choroid plexus, germinal matrix, periventricular, and intraventricular hemorrhages. Survivors exhibit life-long cognitive, behavioral, and motor abnormalities. Available preclinical models do not fully recapitulate the salient features of hemorrhagic EP encountered in humans. In this study, the authors evaluated a novel model using rats that featured tandem insults of transient prenatal intrauterine ischemia (IUI) plus transient postnatal raised intrathoracic pressure (RIP).

Methods

Timed-pregnant Wistar rats were anesthetized and underwent laparotomy on embryonic Day 19. Intrauterine ischemia was induced by clamping the uterine and ovarian vasculature for 20 minutes. Natural birth occurred on embryonic Day 22. Six hours after birth, the pups were subjected to an episode of RIP, induced by injecting glycerol (50%, 13 μl/g intraperitoneally). Control groups included naive, sham surgery, and IUI alone. Pathological, histological, and behavioral analyses were performed on pups up to postnatal Day 52.

Results

Compared with controls, pups subjected to IUI+RIP exhibited significant increases in postnatal mortality and hemorrhages in the choroid plexus, germinal matrix, and periventricular tissues as well as intraventricularly. On postnatal Days 35–52, they exhibited significant abnormalities involving complex vestibulomotor function and rapid spatial learning. On postnatal Day 52, the brain and body mass were significantly reduced.

Conclusions

Tandem insults of IUI plus postnatal RIP recapitulate many features of the hemorrhagic forms of EP found in humans, suggesting that these insults in combination may play important roles in pathogenesis.

Abbreviations used in this paper:

EP = encephalopathy of prematurity; IUI = intrauterine ischemia; MWM = Morris water maze; PBS = phosphate-buffered saline; RIP = raised intrathoracic pressure; ROI = region of interest.
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