Application of novel therapeutic agents for CNS injury: NAAG peptidase inhibitors

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Scopus citations

Abstract

Glutamate excitotoxicity is a significant determinant of traumatic brain injury (TBI) pathophysiology. Elevated glutamate can damage neurons through activation of various glutamate receptors. Excessive extracellular glutamate also initiates astrocyte pathology through excessive uptake of Na+ through sodium-glutamate co-transporters. This chapter discusses a novel strategy for reducing glutamate toxicity following TBI by inhibiting the cleavage of N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate. NAAG is an abundant peptide found in the brain and is released from neurons after intense depolarization and functions as a selective agonist at metabotropic glutamate receptor subtype 3 (mGluR3), which is located on both neurons and astrocytes. NAAG is catabolized into NAA and glutamate by a specific carboxypeptidases. NAAG could play a significant role in modulating glutamate excitotoxicity if its rapid catabolism can be inhibited thereby conferring protection to the traumatized brain in several ways. First, NAAG reduces excessive glutamate release by activation of presynaptic mGluR3 autoreceptors. Second, by inhibiting the cleavage of NAAG into NAA and glutamate a secondary source of synaptic glutamate could be diminished. Third, activation of mGluR3 on astrocytes increases the expression of glutamate transporters thereby facilitating removal of excess glutamate from the synapse. Fourth, inhibiting the accumulation of the NAAG cleavage product, NAA, reduces NAA-Na+ co-transport and subsequent astrocyte Na+ overload. Overload of [Na+]i can initiate astrocyte pathology that subsequently impacts negatively on surrounding neurons. Thus, inhibition of carboxypeptidases represents a novel strategy for reducing glutamate excitotoxicity following TBI through multiple mechanisms. NAAG peptidase inhibition could provide new and important insights into glutamate excitotoxicity and lead to important insights into the dynamics of neuron-astrocyte interactions in TBI pathophysiology.

Original languageEnglish (US)
Title of host publicationBrain Neurotrauma
Subtitle of host publicationMolecular, Neuropsychological, and Rehabilitation Aspects
PublisherCRC Press
Pages549-560
Number of pages12
ISBN (Electronic)9781466565999
ISBN (Print)9781466565982
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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    Lyeth, B. G. (2015). Application of novel therapeutic agents for CNS injury: NAAG peptidase inhibitors. In Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects (pp. 549-560). CRC Press. https://doi.org/10.1201/b18126