Neuroprotection by selective inhibition of inducible nitric oxide synthase after experimental brain contusion

Caroline Gahm, Staffan Holmin, Peter N. Wiklund, Lou Brundin, Tiit Mathiesen

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

The inflammatory response is thought to be important for secondary damage following traumatic brain injury (TBI). The inducible nitric oxide synthase (iNOS) isoform is a mediator in inflammatory reactions and may catalyze substantial synthesis of NO in the injured brain. This study was undertaken to analyze neuronal degeneration and survival, cellular apoptosis and formation of nitrotyrosine following treatment with the iNOS-inhibitor L-N-iminoethyl-lysine (L-NIL) in a model of brain contusion. A brain contusion was produced using a weight-drop device in 30 rats. The animals received treatment with L-NIL or NaCl at 15 min and 12 h after the injury and were sacrificed at 24 h or 6 days after trauma. iNOS activity was measured at 24 h post-trauma by the conversion of L-[U-14C]arginine to L-[U-14C]citrulline and immunohistochemistry for iNOS. Peroxynitrite formation was indirectly assessed by nitrotyrosine (NT) immunohistochemistry. Neuronal degeneration and survival were assessed by Fluoro-Jade (FJ) and NeuN stainings, and cellular death by TUNEL staining. iNOS activity but not iNOS immunoreactivity was significantly reduced in animals that received L-NIL. Neuronal degeneration (FJ) and NT immunoreactivity were significantly reduced at 24 h. Neuronal survival was unchanged at 24 h but increased at 6 days in L-NIL-treated animals. Cellular apoptosis of ED-1 and NeuN positive cells was significantly reduced following L-NIL treatment at 6 days after trauma. We demonstrated neuroprotection by selective inhibition of iNOS after trauma. L-NIL appeared to protect the injured brain by limiting peroxynitrite formation. Our findings support a putative harmful role of iNOS induction early after TBI.

Original languageEnglish
Pages (from-to)1343-1354
Number of pages12
JournalJournal of Neurotrauma
Volume23
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

Keywords

  • Apoptosis
  • L-NIL
  • Neuronal degeneration
  • Nitrotyrosine
  • Traumatic brain injury
  • iNOS

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