The long-term goal of this laboratory continues to be the characterization of N-acetylaspartylglutamate (NAAG) as a major peptide co-neurotransmitter and group II metabotropic glutamate receptor agonist. NAAG peptidase activities regulate peptide levels following synaptic release. Inhibition of NAAG peptidase activities has therapeutic efficacy in animal models of inflammatory pain, allodynia, stroke, diabetic neuropathy, ALS, and schizophrenia. The immediate aims are to contrast the cellular expression of two NAAG peptidases that we have cloned, GCPII and III, and to analyze the consequences of inhibiting their activities. Among the hypotheses to be tested are: 1) GCPII and GCPIII function in distinct cell types and locations to regulate NAAG levels following synaptic release; 2) GCPII knock out mice are dependent upon GCPIII activity to retain normal neurological function; 3) increasing extracellular NAAG levels via peptidase inhibition in the brain and/or at the spinal-sensory level influences inflammatory and neuropathic pain perception via group II mGluRs; 4) NAAG acting via group II mGluRs decreases Substance P and CGRP release and EPSCs at sensory spinal synapses; 5) NAAG peptidase inhibition acts centrally to suppress pain-induced glial activation and peripherally to reduce PGE2-induced hyperalgesia and potentiation of capsaicin responses; 6) mGluRS receptors are negatively coupled to cGMP as well as cAMP; 7) activation of glial group II mGluRs by inhibition of NAAG peptidase increases expression of glutamate transporters, GLT-1 and GLAST. The effect of inhibition of GCPIII on total NAAG peptidase activity will be tested in vivo and in vitro using GCPII knock out mice. The influence of peptidase inhibition on inflammatory and neuropathic pain perception will be determined in the rat model and in wild type, heterozygous and GCPII knock out mice. The influence of elevated NAAG levels in vivo, obtained by inhibition of NAAG peptidase activity, will be tested in rat brain and spinal cord and in transgenic mice expressing GLT-1-GFP and GLAST-GFP fusion proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038080-08
Application #
7407436
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Porter, Linda L
Project Start
2000-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
8
Fiscal Year
2008
Total Cost
$340,303
Indirect Cost
Name
Georgetown University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Walder, Kathryn K; Ryan, Steve B; Bzdega, Tomasz et al. (2013) Immunohistological and electrophysiological evidence that N-acetylaspartylglutamate is a co-transmitter at the vertebrate neuromuscular junction. Eur J Neurosci 37:118-29
Yamada, Toshihiko; Zuo, Daiying; Yamamoto, Tatsuo et al. (2012) NAAG peptidase inhibition in the periaqueductal gray and rostral ventromedial medulla reduces flinching in the formalin model of inflammation. Mol Pain 8:67
Wroblewska, Barbara; Wegorzewska, Iga N; Bzdega, Tomasz et al. (2011) Type 2 metabotropic glutamate receptor (mGluR2) fails to negatively couple to cGMP in stably transfected cells. Neurochem Int 58:176-9
Neale, Joseph H (2011) N-acetylaspartylglutamate is an agonist at mGluR? in vivo and in vitro. J Neurochem 119:891-5
Feng, Jun-Feng; Van, Ken C; Gurkoff, Gene G et al. (2011) Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI. Brain Res 1395:62-73
Neale, Joseph H; Olszewski, Rafal T; Zuo, Daiying et al. (2011) Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family. J Neurochem 118:490-8
Adedoyin, Mary O; Vicini, Stefano; Neale, Joseph H (2010) Endogenous N-acetylaspartylglutamate (NAAG) inhibits synaptic plasticity/transmission in the amygdala in a mouse inflammatory pain model. Mol Pain 6:60
Ghose, Subroto; Gleason, Kelly A; Potts, Bryan W et al. (2009) Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action? Am J Psychiatry 166:812-20
Yamamoto, Tatsuo; Kozikowski, Alan; Zhou, Jia et al. (2008) Intracerebroventricular administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in inflammatory pain. Mol Pain 4:31
Olszewski, Rafal T; Wegorzewska, Marta M; Monteiro, Ana C et al. (2008) Phencyclidine and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors. Biol Psychiatry 63:86-91

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