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.
authors.affiliation: Department of Neurological Surgery, University of California at Davis, One Shields Ave., Davis, CA 95616, USA.
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Feng
authors.forename: Ken C
authors.initials: KC
authors.lastname: Van
authors.forename: Gene G
authors.initials: GG
authors.lastname: Gurkoff
authors.forename: Christina
authors.initials: C
authors.lastname: Kopriva
authors.forename: Rafal T
authors.initials: RT
authors.lastname: Olszewski
authors.forename: Minsoo
authors.initials: M
authors.lastname: Song
authors.forename: Shifeng
authors.initials: S
authors.lastname: Sun
authors.forename: Man
authors.initials: M
authors.lastname: Xu
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Neale
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: David A
authors.initials: DA
authors.lastname: Lowe
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Lyeth
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000502:physiology; D011480:Protease Inhibitors / Q000302:isolation & purification / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; C571450:PGI-02776; D011480:Protease Inhibitors; C486211:ZJ43; D014508:Urea; D043425:Glutamate Carboxypeptidase II