NAAG peptidase inhibitor reduces acute neuronal degeneration and astrocyte damage following lateral fluid percussion TBI in rats

Chunlong Zhong, Xueren Zhao, Jayaprakash Sarva, Alan Kozikowski, Joseph H. Neale, Bruce G. Lyeth

Research output: Contribution to journalArticle

Abstract

Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate associated with excitotoxicity and secondary brain pathology. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) suppresses glutamate transmission through selective activation of presynaptk Group II metaboiropic glutamate receptor subtype 3 (mGluR3). Thus, inhibition of NAAG peptidase activity and the prolong presence of synaptic NAAG were hypothesized to have significant potential for cellular protection following TBI. In the present study, a novel NAAG peptidase inhibitor, ZJ-43, was used in four different doses (0, 50, 100, or 150 mg/kg). Each dose was repeatedly administered i.p. (n = 5/group) by multiple injections at three times (0 time, 8 h, 16 h) after moderate lateral fluid percussion TBI in the rat. An additional group was co-administered ZJ-43 (150 mg/kg) and the Group II mGluR antagonist, LY341495 (1 mg/kg), which was predicted to abolish any protective effects of ZJ-43. Rats were euthanized at 24 h after TBI, and brains were processed with a selective marker for degenerating neurons (Fluoro-Jade B) and a marker for astrocytes (GFAP). Ipsilateral neuronal degeneration and bilateral astrocyte loss in the CA2/3 regions of the hippocampus were quantified using stereological techniques. Compared with vehicle, ZJ-43 significantly reduced the number of the ipsilateral degenerating neurons (p < 0.01) with the greatest neuroprotection at the 50 mg/kg dose. Moreover, LY341495 successfully abolished the protective effects of ZJ-43. 50 mg/kg of ZJ-43 also significantly reduced the ipsilateral astrocyte loss (p < 0.05). We conclude that the NAAG peptidase inhibitor ZJ-43 is a potential novel strategy to reduce both neuronal and astrocyte damage associated with the glutamate escitotosicity after TBI.

Original languageEnglish (US)
Pages (from-to)266-276
Number of pages11
JournalJournal of neurotrauma
Volume22
Issue number2
DOIs
StatePublished - Feb 2005

Keywords

  • Fluid percussion
  • Glutamate
  • Hippocampus
  • Metabotropic glutamate receptor
  • N-acetylaspartylglutamate (NAAG)
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

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