Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI

Jun Feng Feng, Ken C. Van, Gene G Gurkoff, Christina Kopriva, Rafal T. Olszewski, Minsoo Song, Shifeng Sun, Man Xu, Joseph H. Neale, Po Wai Yuen, David A. Lowe, Jia Zhou, Bruce G Lyeth

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Traumatic brain injury (TBI) leads to a rapid and excessive increase in glutamate concentration in the extracellular milieu, which is strongly associated with excitotoxicity and neuronal degeneration. N- acetylaspartylglutamate (NAAG), a prevalent peptide neurotransmitter in the vertebrate nervous system, is released along with glutamate and suppresses glutamate release by actions at pre-synaptic metabotropic glutamate autoreceptors. Extracellular NAAG is hydrolyzed to N-acetylaspartate and glutamate by peptidase activity. In the present study PGI-02776, a newly designed di-ester prodrug of the urea-based NAAG peptidase inhibitor ZJ-43, was tested for neuroprotective potential when administered intraperitoneally 30 min after lateral fluid percussion TBI in the rat. Stereological quantification of hippocampal CA2-3 degenerating neurons at 24 h post injury revealed that 10 mg/kg PGI-02776 significantly decreased the number of degenerating neurons (p < 0.05). Both average latency analysis of Morris water maze performance and assessment of 24-hour memory retention revealed significant differences between sham-TBI and TBI-saline. In contrast, no significant difference was found between sham-TBI and PGI-02776 treated groups in either analysis indicating an improvement in cognitive performance with PGI-02776 treatment. Histological analysis on day 16 post-injury revealed significant cell death in injured animals regardless of treatment. In vitro NAAG peptidase inhibition studies demonstrated that the parent compound (ZJ-43) exhibited potent inhibitory activity while the mono-ester (PGI-02749) and di-ester (PGI-02776) prodrug compounds exhibited moderate and weak levels of inhibitory activity, respectively. Pharmacokinetic assays in uninjured animals found that the di-ester (PGI-02776) crossed the blood-brain barrier. PGI-02776 was also readily hydrolyzed to both the mono-ester (PGI-02749) and the parent compound (ZJ-43) in both blood and brain. Overall, these findings suggest that post-injury treatment with the ZJ-43 prodrug PGI-02776 reduces both acute neuronal pathology and longer term cognitive deficits associated with TBI.

Original languageEnglish (US)
Pages (from-to)62-73
Number of pages12
JournalBrain Research
Volume1395
DOIs
StatePublished - Jun 13 2011

Keywords

  • Glutamate
  • Hippocampus
  • Morris water maze
  • N-acetylaspartylglutamate (NAAG)
  • Traumatic brain injury (TBI)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

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