title: Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain - relation to brain concentration.
abstract: N-acetylated-alpha-linked-acidic peptidase (NAAG peptidase) converts N-acetyl-aspartyl-glutamate (NAAG, mGluR3 agonist) into N-acetyl-aspartate and glutamate. The NAAG peptidase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) had neuroprotective activity in an animal model of stroke and anti-allodynic activity in CCI model despite its uncertain ability to penetrate the blood-brain barrier. The NAAG concentration in brain ECF under basal conditions and its alteration in relation to the brain ECF concentration of 2-PMPA is unclear. We therefore assessed those brain concentrations after i.p. administration of 2-PMPA, using in vivo microdialysis combined with LC/MS/MS analysis. Administration of 2-PMPA (50mg/kg) produced a mean peak concentration of 2-PMPA of 29.66+/-8.1microM. This concentration is about 100,000 fold more than is needed for inhibition of NAAG peptidase, and indicates very good penetration to the brain. Application of 2-PMPA was followed by a linear increase of NAAG-concentration reaching a maximum of 2.89+/-0.42microM at the end of microdialysis. However, during the time the anti-allodynic effects of 2-PMPA were observed, the NAAG concentration in the ECF did not reach levels which are likely to have an impact on any known target. It appears therefore that the observed behavioural effects of 2-PMPA may not be mediated by NAAG nor, in turn, by mGluR3 receptors.
authors.affiliation: Preclinical R & D, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Nagel
authors.forename: Irina
authors.initials: I
authors.lastname: Belozertseva
authors.forename: Sergio
authors.initials: S
authors.lastname: Greco
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kashkin
authors.forename: Andrey
authors.initials: A
authors.lastname: Malyshkin
authors.forename: Aigars
authors.initials: A
authors.lastname: Jirgensons
authors.forename: Elena
authors.initials: E
authors.lastname: Shekunova
authors.forename: Bernd
authors.initials: B
authors.lastname: Eilbacher
authors.forename: Anton
authors.initials: A
authors.lastname: Bespalov
authors.forename: Wojciech
authors.initials: W
authors.lastname: Danysz
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001812:Blood-Brain Barrier; D001923:Brain Chemistry / Q000187:drug effects*; D002908:Chronic Disease; D004151:Dipeptides / Q000032:analysis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D045604:Extracellular Fluid / Q000737:chemistry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D007274:Injections, Intraperitoneal; D008026:Ligation; D008297:Male; D017551:Microdialysis; D023421:Models, Animal; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017288:Pain Threshold / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; C517784:8-chloro-1,4-dioxo-1,2,3,4-tetrahydropyridazino(4,5-b)quinoline; D018712:Analgesics, Non-Narcotic; D004151:Dipeptides; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D011724:Pyridazines; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; C027172:isospaglumic acid; D043425:Glutamate Carboxypeptidase II