title: N-acetyl-aspartyl-glutamate and inhibition of glutamate carboxypeptidases protects against soman-induced neuropathology.
abstract: N-acetyl-aspartyl-glutamate (NAAG) is the most abundant neuropeptide in the mammalian brain. In a variety of animal models of brain injury, the administration of NAAG-related compounds, or inhibitors of glutamate carboxypeptidases (GCPs; the enzymes that hydrolyze NAAG), were shown to be neuroprotective. This study determined the impact of the administration of three NAAG-related compounds, NAAG, β-NAAG (a NAAG homologue resistant to degradation), and 2-phosphonomethyl pentanedioic acid (2-PMPA; an inhibitor of GCP enzymes), on the neuropathology that develops following exposure to the nerve agent, soman. When given 1 min after soman exposure, NAAG-related drug treatments did not alter the survival rate or body weight loss seen 24 h after rats were exposed to soman. Likewise, brain levels of both NAAG and its metabolite, N-acetyl-aspartate (NAA), were substantially decreased 24 h after soman, and in particularly vulnerable brain regions the drug treatments were unable to attenuate the reduction in NAA and NAAG levels. Histochemical study indicated there was a dramatic increase in Fluoro-Jade C (FJC) staining, indicative of neuron cell death, 24 h after soman exposure. However, in the amygdala and in the entorhinal and piriform limbic cortex, which sustained severe neuropathology following soman intoxication, single or combined injections of NAAG compounds and 2-PMPA significantly reduced the number of FJC-positive cells, and effect size estimates suggest that in some brain regions the treatments were effective. The findings suggest that NAAG neurotransmission in the central nervous system is significantly altered by soman exposure, and that the administration of NAAG-related compounds and 2-PMPA reduces neuron cell death in brain regions that sustain severe damage.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
authors.forename: Huifu
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Pharmacology Branch, Research Division, United States Army Medical Research Institute of Chemical Defense (USAMRICD), 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Van Shura
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
authors.forename: HuaZhen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Biomedical Instrumentation Center, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Flora
authors.affiliation: Neurobehavioral Toxicology Branch, Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense (USAMRICD), 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Myers
authors.affiliation: Pharmacology Branch, Research Division, United States Army Medical Research Institute of Chemical Defense (USAMRICD), 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA. Electronic address: Joseph.McCabe@USUHS.edu.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: McCabe
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002619:Chemical Warfare Agents; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D062025:Organophosphate Poisoning / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D012999:Soman; D013997:Time Factors
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D002619:Chemical Warfare Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; C581974:N-acetylaspartyl-beta-linked glutamate; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; C027172:isospaglumic acid; D012999:Soman; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase
keywords: 2-Phosphonomethyl pentanedioic acid (2-PMPA); Brain injury; Effect size; High performance liquid chromatography