Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain – relation to brain concentration
| Autor: | Wojciech Danysz, Aigars Jirgensons, Vladimir A. Kashkin, Bernd Eilbacher, Sergio Greco, A. Malyshkin, Jens Nagel, Anton Bespalov, Elena V. Shekunova, Irina V Belozertseva |
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| Rok vydání: | 2006 |
| Předmět: |
Glutamate Carboxypeptidase II
Male Pain Threshold Agonist Microdialysis medicine.drug_class Drug Evaluation Preclinical Pharmacology Receptors Metabotropic Glutamate Neuroprotection Rats Sprague-Dawley Cellular and Molecular Neuroscience Organophosphorus Compounds In vivo medicine Glutamate carboxypeptidase II Animals Rats Wistar Receptor Ligation Biotransformation Brain Chemistry Dose-Response Relationship Drug Chemistry Chronic pain Glutamate receptor Extracellular Fluid Dipeptides Analgesics Non-Narcotic medicine.disease Sciatic Nerve Rats Pyridazines Neuroprotective Agents Biochemistry Blood-Brain Barrier Chronic Disease Models Animal Quinolines Neuralgia Injections Intraperitoneal |
| Zdroj: | Neuropharmacology. 51:1163-1171 |
| ISSN: | 0028-3908 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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