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

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.

High dosage of agmatine alleviates pentylenetetrazole-induced chronic seizures in rats possibly by exerting an anticonvulsive effect

“…The results from the present study are in accordance with several previous studies demonstrating that high doses of agmatine had marked anticonvulsive effects (3–5). In the present study, only rats treated with a high dose of agmatine (40 and 80 mg/kg/d) demonstrated clear inhibitory effects.…”

Effect of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

“…Fresh drug solutions were administered as follows: phenytoin -120 min; phenobarbital -60 min; and valproate and carbamazepine -30 min, before electroconvulsions and brain sampling for the measurement of antiepileptic drug concentrations. The pretreatment times before testing of the antiepileptic drugs were based upon information about their biological activity from literature and our previous experiments [14,17]. Xanthotoxin (Fig.…”

“…The threshold for maximal electroconvulsions was recorded for 3 different doses of xanthotoxin: 50, 100 and 150 mg/kg. The experimental procedure has been described in more detail in our earlier studies [13][14][15]17,19]. …”

Suicide and the Polyamine System

“…In fact, only agmatine and arginine are able to cross the blood-brain barrier [21]. Systemic injection of agmatine has been shown to substantially increase cortical agmatine concentration in rats [22], even though other studies suggest that 99% of the injected agmatine is rapidly metabolized by peripheral tissues [23]. This is interesting as agmatine is believed to function as a CNS neurotransmitter by binding to NMDA receptors [24], as well as acetylcholine, imidazoline, and serotonin receptors [15].…”