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 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

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

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