Involvement of neuronal nitric oxide synthase in ongoing fetal brain injury following near-term rabbit hypoxia-ischemia

Suma Rao*, Zhenlang Lin, Alexander Drobyshevsky, Lina Chen, Xinhai Ji, Haitao Ji, Yirong Yang, Lei Yu, Matthew Derrick, Richard B. Silverman, Sidhartha Tan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Neuronal nitric oxide synthase (nNOS) and nitric oxide (NO) are implicated in neuronal injury following acute hypoxia-ischemia (HI). Our hypothesis was that NO from nNOS is responsible for ongoing mitochondrial dysfunction in near-term fetal HI. Recently, we synthesized new selective nNOS inhibitors that prevent the cerebral palsy phenotype in our animal model. We tested the efficacy of a selective nNOS inhibitor (JI-8) in fetal brains after in utero HI in our rabbit model. Brain slices at 29 days gestation were obtained after in utero HI, and immediately cultured in medium containing JI-8 or saline for 3-6 days. Mitochondrial membrane integrity and function were determined by flow cytometry using rhodamine 123 and JC-1, and cell death by using propidium iodide. JI-8 decreased NO production in brain slices and also showed significant preservation of mitochondrial function at both 3 and 6 days (p < 0.05) when compared with saline and inducible NOS inhibitor 1400W. There was no difference in cell death. In conclusion, nNOS is involved in ongoing mitochondrial dysfunction after in utero HI. The subacute brain slice model could be a tool for studying the mechanisms involved in ongoing neuronal injury, and for rapidly assessing potential neuroprotectants.

Original languageEnglish (US)
Pages (from-to)288-298
Number of pages11
JournalDevelopmental Neuroscience
Volume33
Issue number3-4
DOIs
StatePublished - Oct 2011

Keywords

  • Brain slice model
  • Hypoxia-ischemia in utero
  • Neuronal nitric oxide synthase
  • Neuronal nitric oxide synthase inhibitor

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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