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Agmatine enhances the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock seizure model

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Abstract

Accumulating evidence indicates that agmatine (AGM—an endogenous neuromodulator/neurotransmitter in the brain) exerts the anticonvulsant action in various in vivo experiments. Therefore, the aim of this study was to assess the influence of AGM on the protective action of numerous conventional and newer antiepileptic drugs [carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA)] in the mouse maximal electroshock seizure (MES) model. Results indicate that AGM (up to 100 mg/kg, i.p., 45 min before the test) neither altered the threshold for electroconvulsions nor protected the animals against MES-induced seizures in mice. Moreover, AGM (100 mg/kg, i.p.) significantly enhanced the anticonvulsant effects of PB and VPA in the MES test by reducing their ED50 values from 22.54 to 16.82 mg/kg (P < 0.01) for PB, and from 256.1 to 210.6 mg/kg (P < 0.05) for VPA, respectively. In contrast, AGM at 100 mg/kg (i.p.) had no significant effect on the antielectroshock action of the remaining drugs tested (CBZ, LTG, OXC, PHT, and TPM) in mice. Estimation of total brain PB and VPA concentrations revealed that the observed interactions between AGM and PB or VPA in the MES test were pharmacodynamic in nature because neither total brain PB, nor total brain VPA concentrations were altered after i.p. administration of AGM at 100 mg/kg. Moreover, none of the examined combinations of AGM (100 mg/kg) with CBZ, LTG, OXC, PB, PHT, TPM, and VPA (at their ED50 values from the MES test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no acute adverse effects in animals. In conclusion, one can ascertain that the selective potentiation of the antielectroshock action of PB and VPA by AGM, lack of any pharmacokinetic interactions between drugs and no acute adverse effects, make the combinations of AGM with PB or VPA of pivotal importance for epileptic patients. It seems that modulation of AGM concentration in the brain may occur favorable in further clinical practice.

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Acknowledgments

This study was supported by a grant from Medical University of Lublin (DS 475/2006–2008). The authors are grateful for the generous gifts of VPA from ICN-Polfa S.A. (Rzeszow, Poland) and CBZ from Polpharma S.A. (Starogard, Poland).

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Authors and Affiliations

  1. Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland

    Jarogniew J. Luszczki, Remigiusz Czernecki, Katarzyna Wojtal, Kinga K. Borowicz & Stanislaw J. Czuczwar

  2. Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950, Lublin, Poland

    Jarogniew J. Luszczki & Stanislaw J. Czuczwar

  3. Department of Neurology, Neuropsychiatric Hospital, Grunwaldzka 47, 25-736, Kielce, Poland

    Remigiusz Czernecki

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  1. Jarogniew J. Luszczki
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  2. Remigiusz Czernecki
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  4. Kinga K. Borowicz
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Correspondence to Jarogniew J. Luszczki.

Additional information

The results of this study were presented in part at the “11th Congress of the European Federation of Neurological Societies” Brussels, Belgium, 25–28 August, 2007 [abstract in 2007, Eur J Neurol 14(Suppl 1):210].

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Luszczki, J.J., Czernecki, R., Wojtal, K. et al. Agmatine enhances the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock seizure model. J Neural Transm 115, 1485–1494 (2008). https://doi.org/10.1007/s00702-008-0046-3

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