Open AccessUpregulation of cystathione β‐synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury
Author(s) -
Lechpammer Mirna,
Tran Yen P.,
Wintermark Pia,
MartínezCerdeño Veronica,
Krishnan Viswanathan V.,
Ahmed Waseem,
Berman Robert F.,
Jensen Frances E.,
Nudler Evgeny,
Zagzag David
Publication year - 2017
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12421
Subject(s) - ribosomal protein s6 , pi3k/akt/mtor pathway , hypoxia (environmental) , downregulation and upregulation , mechanistic target of rapamycin , hippocampal formation , medicine , endocrinology , p70 s6 kinase 1 , neuroscience , chemistry , biology , signal transduction , microbiology and biotechnology , biochemistry , organic chemistry , oxygen , gene
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.