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2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice.
Eur J Pharmacol. 2006 Feb 15; 531(1-3):66-73.EJ

Abstract

This study examined the effect of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent and selective inhibitor of glutamate carboxypeptidase II (GCP II), an enzyme releasing glutamate and N-acetyl-aspartate from synaptical terminals, on the electroconvulsive threshold in mice. Moreover, the influence of 2-PMPA on the anticonvulsant activities of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was evaluated in the maximal electroshock-induced seizure test in mice. Results indicated that 2-PMPA (at a dose range of 50-200 mg/kg, i.p.) raised the electroconvulsive threshold in mice dose-dependently. Linear regression analysis of dose-response relationship between the doses of 2-PMPA and their corresponding threshold values allowed the calculation of threshold increasing dose by 20% (TID20), which was 109.2 mg/kg. Moreover, 2-PMPA administered i.p. at a constant dose of 150 mg/kg (the dose increasing the threshold for electroconvulsions) enhanced significantly the anticonvulsant action of valproate, by reducing its median effective dose (ED50) from 281.4 to 230.1 mg/kg (P<0.05). In contrast, 2-PMPA at the lower dose of 100 mg/kg (i.p.) had no impact on the antiseizure activity of valproate in the maximal electroshock-induced seizure test. Likewise, 2-PMPA at 100 and 150 mg/kg did not affect the antiseizure action of carbamazepine, phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Additionally, none of the combinations investigated between 2-PMPA (150 mg/kg, i.p.) and carbamazepine, phenobarbital, phenytoin and valproate (at their ED50 values) produced motor coordination impairment in the chimney test. Pharmacokinetic evaluation of interaction between 2-PMPA and valproate revealed that 2-PMPA at 150 mg/kg selectively increased total brain concentrations of valproate, remaining simultaneously without any effect on free plasma concentrations of valproate, indicating a pharmacokinetic nature of observed interaction in the maximal electroshock-induced seizures in mice. Based on our preclinical data, it may be concluded that 2-PMPA possesses a seizure modulating property by increasing the electroconvulsive threshold. The reduction of glutamate neurotransmission in the brain, as a consequence of inhibition of GCP II activity by 2-PMPA, was however insufficient to enhance the anticonvulsant activity of conventional antiepileptic drugs, except for valproate, whose antiseizure action against maximal electroconvulsions was potentiated by 2-PMPA. Unfortunately, the favourable interaction between 2-PMPA and valproate was associated with a pharmacokinetic increase in total brain valproate concentrations.

Authors+Show Affiliations

Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland. jluszczki@yahoo.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16403497

Citation

Luszczki, Jarogniew J., et al. "2-phosphonomethyl-pentanedioic Acid (glutamate Carboxypeptidase II Inhibitor) Increases Threshold for Electroconvulsions and Enhances the Antiseizure Action of Valproate Against Maximal Electroshock-induced Seizures in Mice." European Journal of Pharmacology, vol. 531, no. 1-3, 2006, pp. 66-73.
Luszczki JJ, Mohamed M, Czuczwar SJ. 2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice. Eur J Pharmacol. 2006;531(1-3):66-73.
Luszczki, J. J., Mohamed, M., & Czuczwar, S. J. (2006). 2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice. European Journal of Pharmacology, 531(1-3), 66-73.
Luszczki JJ, Mohamed M, Czuczwar SJ. 2-phosphonomethyl-pentanedioic Acid (glutamate Carboxypeptidase II Inhibitor) Increases Threshold for Electroconvulsions and Enhances the Antiseizure Action of Valproate Against Maximal Electroshock-induced Seizures in Mice. Eur J Pharmacol. 2006 Feb 15;531(1-3):66-73. PubMed PMID: 16403497.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice. AU - Luszczki,Jarogniew J, AU - Mohamed,Mohamed, AU - Czuczwar,Stanislaw J, Y1 - 2006/01/03/ PY - 2005/11/16/received PY - 2005/11/22/accepted PY - 2006/1/13/pubmed PY - 2006/4/19/medline PY - 2006/1/13/entrez SP - 66 EP - 73 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 531 IS - 1-3 N2 - This study examined the effect of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent and selective inhibitor of glutamate carboxypeptidase II (GCP II), an enzyme releasing glutamate and N-acetyl-aspartate from synaptical terminals, on the electroconvulsive threshold in mice. Moreover, the influence of 2-PMPA on the anticonvulsant activities of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was evaluated in the maximal electroshock-induced seizure test in mice. Results indicated that 2-PMPA (at a dose range of 50-200 mg/kg, i.p.) raised the electroconvulsive threshold in mice dose-dependently. Linear regression analysis of dose-response relationship between the doses of 2-PMPA and their corresponding threshold values allowed the calculation of threshold increasing dose by 20% (TID20), which was 109.2 mg/kg. Moreover, 2-PMPA administered i.p. at a constant dose of 150 mg/kg (the dose increasing the threshold for electroconvulsions) enhanced significantly the anticonvulsant action of valproate, by reducing its median effective dose (ED50) from 281.4 to 230.1 mg/kg (P<0.05). In contrast, 2-PMPA at the lower dose of 100 mg/kg (i.p.) had no impact on the antiseizure activity of valproate in the maximal electroshock-induced seizure test. Likewise, 2-PMPA at 100 and 150 mg/kg did not affect the antiseizure action of carbamazepine, phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Additionally, none of the combinations investigated between 2-PMPA (150 mg/kg, i.p.) and carbamazepine, phenobarbital, phenytoin and valproate (at their ED50 values) produced motor coordination impairment in the chimney test. Pharmacokinetic evaluation of interaction between 2-PMPA and valproate revealed that 2-PMPA at 150 mg/kg selectively increased total brain concentrations of valproate, remaining simultaneously without any effect on free plasma concentrations of valproate, indicating a pharmacokinetic nature of observed interaction in the maximal electroshock-induced seizures in mice. Based on our preclinical data, it may be concluded that 2-PMPA possesses a seizure modulating property by increasing the electroconvulsive threshold. The reduction of glutamate neurotransmission in the brain, as a consequence of inhibition of GCP II activity by 2-PMPA, was however insufficient to enhance the anticonvulsant activity of conventional antiepileptic drugs, except for valproate, whose antiseizure action against maximal electroconvulsions was potentiated by 2-PMPA. Unfortunately, the favourable interaction between 2-PMPA and valproate was associated with a pharmacokinetic increase in total brain valproate concentrations. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/16403497/2_phosphonomethyl_pentanedioic_acid__glutamate_carboxypeptidase_II_inhibitor__increases_threshold_for_electroconvulsions_and_enhances_the_antiseizure_action_of_valproate_against_maximal_electroshock_induced_seizures_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(05)01248-3 DB - PRIME DP - Unbound Medicine ER -