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
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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