title: Upregulation of cystathionine β-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Lechpammer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.
authors.forename: Yen P
authors.initials: YP
authors.lastname: Tran
authors.affiliation: Department of Pediatrics, Division of Newborn Medicine, Montréal Children's Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Pia
authors.initials: P
authors.lastname: Wintermark
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.|MIND Institute, University of California Davis, Sacramento, CA.|Institute for Pediatric Regenerative Medicine and Shriners Hospital for Children of Northern California, Sacramento, CA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Martínez-Cerdeño
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.
authors.forename: Viswanathan V
authors.initials: VV
authors.lastname: Krishnan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.
authors.forename: Waseem
authors.initials: W
authors.lastname: Ahmed
authors.affiliation: MIND Institute, University of California Davis, Sacramento, CA.|Department of Neurological Surgery, University of California Davis, Sacramento, CA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, New York University School of Medicine, New York, NY.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Nudler
authors.affiliation: 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.
authors.forename: David
authors.identifier: 0000-0002-2331-0613
authors.initials: D
authors.lastname: Zagzag
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002755:Choice Behavior / Q000502:physiology; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000068338:Everolimus / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008124:Locomotion; D000076104:Oligodendrocyte Transcription Factor 2 / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D066127:White Matter / Q000378:metabolism / Q000473:pathology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003541:Cystathionine beta-Synthase; D000068338:Everolimus; D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D000076104:Oligodendrocyte Transcription Factor 2; D019893:Ribosomal Protein S6 Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: CBS; autism; brain injury; hypoxia; mTOR; prematurity