Comparison of iNOS Inhibition by Antisense and Pharmacological Inhibitors after Spinal Cord Injury

Damien D Pearse, K. Chatzipanteli, Alexander Marcillo, Mary B Bunge, W. Dalton Dietrich

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Inducible nitric oxide synthase (iNOS) is a key mediator of inflammation during pathological conditions. We examined, through the use of selective iNOS inhibitors, the role of iNOS in specific pathophysiological processes after spinal cord injury (SCI), including astrogliosis, blood-spinal cord barrier (BSCB) permeability, polymorphonuclear leukocyte infiltration, and neuronal cell death. Administration of iNOS antisense oligonucleotides (ASOs) (intraspinally at 3 h) or the pharmacological inhibitors, N-[3(Aminomethyl) benzyl] acetamidine (1400W) (i.v./i.p. 3 and 9 h) or aminoguanidine (i.p. at 3 and 9 h) after moderate contusive injury decreased the number of iNOS immunoreactive cells at the injury site by 65.6% (iNOS ASOs), 62.1% (1400W), or 59% (aminoguanidine) 24 h postinjury. iNOS activity was reduced 81.8% (iNOS ASOs), 56.7% (1400W), or 67.9% (aminoguanidine) at this time. All iNOS inhibitors reduced the degree of BSCB disruption (plasma leakage of rat immunoglobulins), with iNOS ASO inhibition being more effective (reduced by 58%). Neutrophil accumulation within the injury site was significantly reduced by iNOS ASOs and 1400W by 78.8% and 20.9%, respectively. Increased astrogliosis was diminished with iNOS ASOs but enhanced following aminoguanidine. Detection of necrotic and apoptotic neuronal cell death by propidium iodide and an FITC-conjugated Annexin V antibody showed that iNOS inhibition could significantly retard neuronal cell death rostral and caudal to the injury site. These novel findings indicate that acute inhibition of iNOS is beneficial in reducing several pathophysiological processes after SCI. Furthermore, we demonstrate that the antisense inhibition of iNOS is more efficacious than currently available pharmacological agents.

Original languageEnglish
Pages (from-to)1096-1107
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume62
Issue number11
StatePublished - Nov 1 2003

Fingerprint

Nitric Oxide Synthase Type II
Spinal Cord Injuries
Pharmacology
Antisense Oligonucleotides
Cell Death
Wounds and Injuries
Spinal Cord
Neutrophils
Inflammation Mediators
Propidium
Fluorescein-5-isothiocyanate
Annexin A5
Immunoglobulins
Permeability

Keywords

  • 1400W
  • Aminoguanidine
  • Antisense
  • Inducible nitric oxide synthase
  • Spinal cord injury

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Comparison of iNOS Inhibition by Antisense and Pharmacological Inhibitors after Spinal Cord Injury. / Pearse, Damien D; Chatzipanteli, K.; Marcillo, Alexander; Bunge, Mary B; Dalton Dietrich, W.

In: Journal of Neuropathology and Experimental Neurology, Vol. 62, No. 11, 01.11.2003, p. 1096-1107.

Research output: Contribution to journalArticle

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