Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion

doi:10.1016/S0387-7604(99)00018-2

Brain and Development

Volume 21, Issue 4, 1 June 1999, Pages 248-252

https://doi.org/10.1016/S0387-7604(99)00018-2 Get rights and content

Abstract

We conducted a chronic preparation experiment involving near term fetal sheep to evaluate the contribution of umbilical cord occlusion to fetal brain injury. In experimental groups (n=11), complete cord occlusion for 3 min followed by 5 min release, repeated 5 times were performed at 3 days after initial surgery. Instrumental cases without cord occlusion (n=3) and uninstrumental twins (n=6) were also examined as controls. Multiple necrotic foci predominantly in the periventricular white matter were found in the fetal brains examined at 1–3 days after cord occlusion. To estimate the contribution of early axonal and glial reaction to brain injury the following immunohistochemical study was performed. In the lesions, coagulation necrosis, axonal swelling and microglial activation were demonstrated with amyloid precursor protein or ionized calcium binding adapter molecule 1 immunohistochemistry. The induction of tumor necrosis factor alpha and inducible nitric oxide synthase were also detected immunohistochemically in the microglia at 1 and 3 days after cord occlusion. In contrast, the reaction of glial fibrillary acidic protein positive astrocytes was faint at 1 day after occlusion, but the induction of cyclooxygenase-2 was observed. These findings suggest the glial reaction of cytokines and free radicals induced by fetal hypoxia may contribute to the occurrence of brain injury.

Introduction

Hypoxic-ischemic brain lesions are major cause of cerebral palsy in childhood [1]. It is speculated that hypoxia-ischemia occurs in the intrauterine period and hypoxic-ischemic brain lesions develop in the perinatal period. Prenatal periventricular leukomalacia (PVL) is often found in autopsied neonates, but its pathogenesis is incompletely understood 2, 3, 4. In our previous animal study involving near term fetal sheep, brief repeated cord occlusion caused fetal hypoxia, acidosis, brain hypoperfusion, and free radical generation leading to several brain lesions [5]. In this animal model, ischemia-reperfusion is a major factor for the development of brain lesions [6], but the mechanism underlying their development is not clear. In the lesions, a tissue reaction consisting of coagulation necrosis, macrophage infiltration and reactive astrogliosis occurs. For the progression of the tissue reaction, cytokines [7]and free radical generation [8]may be important factors for the development of brain lesions. To clarify the role of glial cells in fetal brain damage, we performed pathological analysis of the axon and glial reactions in and around lesions by means of immunohistochemical methods.

Section snippets

Materials and methods

The chronic surgical procedures were described previously 5, 9. Briefly, preparatory procedures were performed on 14 pregnant ewes, six of which had twin pregnancies, at 118–127 days of gestation. After anesthesia and lower abdominal incision, catheters were placed in the right carotid artery and jugular vein of fetuses, and the amniotic cavity. Electrodes for electrocardiography were placed on the fetal thorax and a vascular occluder on the umbilical cord. After a 4 day recovery period, 11

Results

The distribution and grading of the fetal brain lesions, and the results of immunohistochemistry are summarized in Table 1. In the experimental occlusion group, necrotic lesions were most commonly detected in the periventricular white matter (64%), accompanied by focal necrosis in the cerebral cortex (45%) and/or thalamus (64%). Less frequently, hypoxic-ischemic lesions were detected in the basal ganglia (case 10), hippocampus (case 5 and 10), cerebellum (cases 4, 5 and 8), and brain stem (case

Discussion

In this study on fetal sheep brain lesions induced by repeated total cord occlusion, we demonstrated multiple necrotic foci of early axonal damage on APP immunohistochemistry, and the early contribution of microglia with induction of TNF-a and iNOS, as well as astrocytes with induction of COX-2 to the formation of necrotic foci by means of immunohistochemical methods. Experimental studies to gain an insight into fetal brain lesions were described previously, several animal species being used.

Acknowledgements

This study was supported by grants from the Ministry of Health and Welfare, and the Ministry of Education, Science and Culture, Japan.

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Original articleEarly axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Pediatr Neurol

Pediatr Neurol

Trends Neurosci

Biochem Biophys Res Commum

Am J Obstet Gynecol

Am J Obstet Gynecol

Pediatr Neurol

Brain Res Mol Brain Res

Pediatr Neurol

Trends Neurosci

Prostaglandins

Original article
Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion