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Brain Pathol. 2017 Jul;27(4):449-458. doi: 10.1111/bpa.12421. Epub 2016 Aug 28.

Upregulation of cystathionine β-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury.

Author information

1
Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.
2
Department of Pediatrics, Division of Newborn Medicine, Montréal Children's Hospital, McGill University, Montréal, QC, Canada.
3
MIND Institute, University of California Davis, Sacramento, CA.
4
Institute for Pediatric Regenerative Medicine and Shriners Hospital for Children of Northern California, Sacramento, CA.
5
Department of Neurological Surgery, University of California Davis, Sacramento, CA.
6
Department of Neurology, University of Pennsylvania, Philadelphia, PA.
7
Howard Hughes Medical Institute and Department of Biochemistry, New York University School of Medicine, New York, NY.
8
Departments of Pathology and Neurosurgery, Division of Neuropathology, Microvascular and Molecular Neuro-Oncology Laboratory, Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY.

Erratum in

Abstract

Encephalopathy of prematurity (EOP) is a complex form of cerebral injury that occurs in the setting of hypoxia-ischemia (HI) in premature infants. Using a rat model of EOP, we investigated whether neonatal HI of the brain may alter the expression of cystathionine β-synthase (CBS) and the components of the mammalian target of rapamycin (mTOR) signaling. We performed unilateral carotid ligation and induced HI (UCL/HI) in Long-Evans rats at P6 and found increased CBS expression in white matter (i.e. corpus callosum, cingulum bundle and external capsule) as early as 24 h (P7) postprocedure. CBS remained elevated through P21, and, to a lesser extent, at P40. The mTOR downstream target 70 kDa ribosomal protein S6 kinase (p70S6K and phospho-p70S6K) and 40S ribosomal protein S6 (S6 and phospho-S6) were also overexpressed at the same time points in the UCL/HI rats compared to healthy controls. Overexpression of mTOR components was not observed in rats treated with the mTOR inhibitor everolimus. Behavioral assays performed on young rats (postnatal day 35-37) following UCL/HI at P6 indicated impaired preference for social novelty, a behavior relevant to autism spectrum disorder, and hyperactivity. Everolimus restored behavioral patterns to those observed in healthy controls. A gait analysis has shown that motor deficits in the hind paws of UCL/HI rats were also significantly reduced by everolimus. Our results suggest that neonatal HI brain injury may inflict long-term damage by upregulation of CBS and mTOR signaling. We propose this cascade as a possible new molecular target for EOP-a still untreatable cause of autism, hyperactivity and cerebral palsy.

KEYWORDS:

CBS; autism; brain injury; hypoxia; mTOR; prematurity

PMID:
27465493
DOI:
10.1111/bpa.12421
[Indexed for MEDLINE]

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