Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

Yonggang Li, Pamela J Lein, Cuimei Liu, Donald A. Bruun, Cecilia R Giulivi, Gregory D. Ford, Teclemichael Tewolde, Catherine Ross-Inta, Byron D. Ford

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague-Dawley rats were pretreated with pyridostigmine (0.1. mg/kg BW, i.m.) and atropine methylnitrate (20. mg/kg BW, i.m.) prior to DFP (9. mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2. μg/kg BW, i.a) or NRG-GGF2 (48. μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24. h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1. h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication.

Original languageEnglish (US)
Pages (from-to)194-204
Number of pages11
JournalToxicology and Applied Pharmacology
Volume262
Issue number2
DOIs
StatePublished - Jul 15 2012

Keywords

  • Apoptosis
  • Delayed neurotoxicity
  • Diisopropylflurophosphate (DFP)
  • Neuroprotection
  • Organophosphate
  • Oxidative stress
  • Rat model

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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