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 journalArticle

20 Citations (Scopus)

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

Fingerprint

Glutamate Carboxypeptidase II
Prodrugs
Protease Inhibitors
Wounds and Injuries
Glutamic Acid
Esters
Percussion
Neurons
Autoreceptors
PGI-02776
Traumatic Brain Injury
Blood-Brain Barrier
Nervous System
Neurotransmitter Agents
Vertebrates
Urea
Peptide Hydrolases
Cell Death
Pharmacokinetics
Pathology

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

Cite this

Feng, J. F., Van, K. C., Gurkoff, G. G., Kopriva, C., Olszewski, R. T., Song, M., ... Lyeth, B. G. (2011). Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI. Brain Research, 1395, 62-73. https://doi.org/10.1016/j.brainres.2011.04.022

Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI. / Feng, Jun Feng; Van, Ken C.; Gurkoff, Gene G.; Kopriva, Christina; Olszewski, Rafal T.; Song, Minsoo; Sun, Shifeng; Xu, Man; Neale, Joseph H.; Yuen, Po Wai; Lowe, David A.; Zhou, Jia; Lyeth, Bruce G.

In: Brain Research, Vol. 1395, 13.06.2011, p. 62-73.

Research output: Contribution to journalArticle

Feng, JF, Van, KC, Gurkoff, GG, Kopriva, C, Olszewski, RT, Song, M, Sun, S, Xu, M, Neale, JH, Yuen, PW, Lowe, DA, Zhou, J & Lyeth, BG 2011, 'Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI', Brain Research, vol. 1395, pp. 62-73. https://doi.org/10.1016/j.brainres.2011.04.022
Feng, Jun Feng ; Van, Ken C. ; Gurkoff, Gene G. ; Kopriva, Christina ; Olszewski, Rafal T. ; Song, Minsoo ; Sun, Shifeng ; Xu, Man ; Neale, Joseph H. ; Yuen, Po Wai ; Lowe, David A. ; Zhou, Jia ; Lyeth, Bruce G. / Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI. In: Brain Research. 2011 ; Vol. 1395. pp. 62-73.
@article{60d6dafc7c2a414d93fdc7f8103ba0a5,
title = "Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI",
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.",
keywords = "Glutamate, Hippocampus, Morris water maze, N-acetylaspartylglutamate (NAAG), Traumatic brain injury (TBI)",
author = "Feng, {Jun Feng} and Van, {Ken C.} and Gurkoff, {Gene G.} and Christina Kopriva and Olszewski, {Rafal T.} and Minsoo Song and Shifeng Sun and Man Xu and Neale, {Joseph H.} and Yuen, {Po Wai} and Lowe, {David A.} and Jia Zhou and Lyeth, {Bruce G.}",
year = "2011",
month = "6",
day = "13",
doi = "10.1016/j.brainres.2011.04.022",
language = "English (US)",
volume = "1395",
pages = "62--73",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

TY - JOUR

T1 - Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI

AU - Feng, Jun Feng

AU - Van, Ken C.

AU - Gurkoff, Gene G.

AU - Kopriva, Christina

AU - Olszewski, Rafal T.

AU - Song, Minsoo

AU - Sun, Shifeng

AU - Xu, Man

AU - Neale, Joseph H.

AU - Yuen, Po Wai

AU - Lowe, David A.

AU - Zhou, Jia

AU - Lyeth, Bruce G.

PY - 2011/6/13

Y1 - 2011/6/13

N2 - 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.

AB - 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.

KW - Glutamate

KW - Hippocampus

KW - Morris water maze

KW - N-acetylaspartylglutamate (NAAG)

KW - Traumatic brain injury (TBI)

UR - http://www.scopus.com/inward/record.url?scp=79957926348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957926348&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2011.04.022

DO - 10.1016/j.brainres.2011.04.022

M3 - Article

C2 - 21565332

AN - SCOPUS:79957926348

VL - 1395

SP - 62

EP - 73

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -