Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain development and motor function

Journal of Neuroinflammation

Shenandoah Robinson¹  Rebekah Mannix¹  Julian Flores¹  Daniel J Firl¹  Jacqueline Berglass¹  Christopher J Corbett¹  Lauren L Jantzie² 

[1] Departments of Neurology and Neurosurgery, F.M. Kirby Center for Neurobiology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA;Current address: Department of Pediatrics, UNM, Office of Pediatric Research, MSC10 5590, 1 University of New Mexico, Albuquerque, NM 87131, USA

关键词: Motor deficit;    Gait;    Neurofilament;    Myelin;    Prematurity;    Erythropoietin;    Lipopolysaccharide;    Inflammation;    Hypoxia-ischemia;    Preterm;   

Others  :  1151202
DOI  :  10.1186/1742-2094-11-131

 received in 2014-05-21, accepted in 2014-07-15,  发布年份 2014

【 摘 要 】

Background

Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month.

Methods

Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction.

Results

Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001).

Conclusions

Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.

【 授权许可】

   
2014 Jantzie et al.; licensee BioMed Central Ltd.

【 图 表 】

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