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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

Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.
Department of Pediatrics, Division of Newborn Medicine, Montréal Children's Hospital, McGill University, Montréal, QC, Canada.
MIND Institute, University of California Davis, Sacramento, CA.
Institute for Pediatric Regenerative Medicine and Shriners Hospital for Children of Northern California, Sacramento, CA.
Department of Neurological Surgery, University of California Davis, Sacramento, CA.
Department of Neurology, University of Pennsylvania, Philadelphia, PA.
Howard Hughes Medical Institute and Department of Biochemistry, New York University School of Medicine, New York, NY.
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


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.


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

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