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

Mirna Lechpammer, Yen P. Tran, Pia Wintermark, Veronica Martinez-Cerdeno, Viswanathan V Krishnan, Waseem Ahmed, Robert F Berman, Frances E. Jensen, Evgeny Nudler, David Zagzag

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBrain Pathology
DOIs
StateAccepted/In press - 2016

Fingerprint

70-kDa Ribosomal Protein S6 Kinases
S 6
Sirolimus
Brain Injuries
Up-Regulation
Ligation
Brain Diseases
Ischemia
Ribosomal Protein S6
Cystathionine
Brain Hypoxia-Ischemia
Long Evans Rats
Corpus Callosum
Cerebral Palsy
Autistic Disorder
Gait
Premature Infants
Wounds and Injuries
Hypoxia
Everolimus

Keywords

  • Autism
  • Brain injury
  • CBS
  • Hypoxia
  • MTOR
  • Prematurity

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

Cite this

Upregulation of cystathione β-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury. / Lechpammer, Mirna; Tran, Yen P.; Wintermark, Pia; Martinez-Cerdeno, Veronica; Krishnan, Viswanathan V; Ahmed, Waseem; Berman, Robert F; Jensen, Frances E.; Nudler, Evgeny; Zagzag, David.

In: Brain Pathology, 2016.

Research output: Contribution to journalArticle

@article{a28179ce3e954b33acc9f170b1db38e3,
title = "Upregulation of cystathione 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.",
keywords = "Autism, Brain injury, CBS, Hypoxia, MTOR, Prematurity",
author = "Mirna Lechpammer and Tran, {Yen P.} and Pia Wintermark and Veronica Martinez-Cerdeno and Krishnan, {Viswanathan V} and Waseem Ahmed and Berman, {Robert F} and Jensen, {Frances E.} and Evgeny Nudler and David Zagzag",
year = "2016",
doi = "10.1111/bpa.12421",
language = "English (US)",
journal = "Brain Pathology",
issn = "1015-6305",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Upregulation of cystathione β-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury

AU - Lechpammer, Mirna

AU - Tran, Yen P.

AU - Wintermark, Pia

AU - Martinez-Cerdeno, Veronica

AU - Krishnan, Viswanathan V

AU - Ahmed, Waseem

AU - Berman, Robert F

AU - Jensen, Frances E.

AU - Nudler, Evgeny

AU - Zagzag, David

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Autism

KW - Brain injury

KW - CBS

KW - Hypoxia

KW - MTOR

KW - Prematurity

UR - http://www.scopus.com/inward/record.url?scp=84983507705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983507705&partnerID=8YFLogxK

U2 - 10.1111/bpa.12421

DO - 10.1111/bpa.12421

M3 - Article

C2 - 27465493

AN - SCOPUS:84983507705

JO - Brain Pathology

JF - Brain Pathology

SN - 1015-6305

ER -