Acute molecular perturbation of inducible nitric oxide synthase with an antisense approach enhances neuronal preservation and functional recovery after contusive spinal cord injury

Dominic M. Maggio, Katina Chatzipanteli, Neil Masters, Samik P. Patel, W. Dalton Dietrich, Damien D. Pearse

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Inducible nitric oxide synthase (iNOS) is a key mediator of inflammation and oxidative stress produced during pathological conditions, including neurodegenerative diseases and central nervous system (CNS) injury. iNOS is responsible for the formation of high levels of nitric oxide (NO). The production of highly reactive and cytotoxic NO species, such as peroxynitrite, plays an important role in secondary tissue damage. We have previously demonstrated that acute administration of iNOS antisense oligonucleotides (ASOs) 3 h after moderate contusive spinal cord injury (SCI) potently inhibits iNOS-mediated increases in NO levels, leading to reduced blood-spinal cord barrier permeability, decreased neutrophil accumulation, and less neuronal cell death. In the current study we investigated if iNOS ASOs could also provide long-term (10-week) histological and behavioral improvements after moderate thoracic T8 contusive SCI. Adult rats were randomly assigned to three groups (n=10/group): SCI alone, SCI and mixed base control oligonucleotides (MBOs), or SCI and iNOS ASOs (200 nM). Oligonucleotides were administered by spinal superfusion 3 h after injury. Behavioral analysis (Basso-Beattie-Bresnahan [BBB] score and subscore) was employed weekly for 10 weeks post-SCI. Although animals treated with iNOS ASOs demonstrated no significant differences in BBB scores compared to controls, subscore analysis revealed a significant improvement in foot positioning, trunk stability, and tail clearance. Histologically, while no gross improvement in preserved white and gray matter was observed, greater numbers of surviving neurons were present adjacent to the lesion site in iNOS ASO-treated animals than controls. These results support the effectiveness of targeting iNOS acutely as a therapeutic approach after SCI.

Original languageEnglish (US)
Pages (from-to)2244-2249
Number of pages6
JournalJournal of neurotrauma
Volume29
Issue number12
DOIs
StatePublished - Aug 10 2012

Keywords

  • neuronal cell death
  • nitric oxide
  • nitric oxide synthase
  • oligonucleotides
  • spinal cord injury

ASJC Scopus subject areas

  • Clinical Neurology

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