Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain – relation to brain concentration

  title={Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain – relation to brain concentration},
  author={Jens Nagel and Irina V. Belozertseva and Sergio Greco and Vladimir A. Kashkin and Andrey A Malyshkin and Aigars Jirgensons and E. V. Shekunova and Bernd Eilbacher and Anton Bespalov and Wojciech Danysz},

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors

Local administration of N‐acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats

Understanding of the role of this peptide in sensory neurons is extended and the potential for treatment of inflammatory pain via local application of NAAG peptidase inhibitors at doses that may have little or no central nervous system effects is revealed.

Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG)

These findings demonstrate that MDPV withdrawal produces dysregulation in the endogenous NAAG-GCPII signaling pathway in corticolimbic circuitry.

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

It is reported that E2072 attenuates hyperalgesia and nerve conduction velocity deficits in preclinical rodent models of neuropathic pain and oxaliplatin-induced neuropathy, and shows no interference with the antineoplastic efficacy of oxali Platin in mice bearing leukemia.

Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies

Monitoring GCP activity in human skin after administration of G CP inhibitors could be readily used as PD marker in the clinical development of GCP inhibitors.

N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors

The data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors, and encourage the use of NAC for the experimental treatment of inflammatory pain in humans.

Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer.

This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies, and outlines the development of G CPII-specific small-molecule compounds and their use in preclinical and clinical settings.



The Regional Distribution of N‐Acetylaspartylglutamate (NAAG) and Peptidase Activity Against NAAG in the Rat Nervous System

The hypothesis that hydrolysis of NAAG to glutamate and N‐acetylaspartate is a consistent aspect of the physiology and metabolism of this peptide after synaptic release is supported.

N-Acetylaspartate in neuropsychiatric disorders

High concentrations of N-acetylaspartylglutamate (NAAG) selectively activate NMDA receptors on mouse spinal cord neurons in cell culture

Analysis of the dipeptide by high- pressure liquid chromatography showed no evidence of contamination by excitatory amino acids, suggesting that NAAG has an intrinsic, although weak, neuroexcitatory action on spinal neurons.

Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury

It is demonstrated that the newly described 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion, indicating that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.