Abstract
BackgroundThe effects induced by administering the anticonvulsant lamotrigine, the preferential inhibitor of neuronal nitric oxide synthase 7-nitroindazole and the precursor of NO synthesis L-arginine, alone or in combination, on an experimental model of partial complex seizures (maximal dentate gyrus activation) were studied in urethane anaesthetized rats. The epileptic activity of the dentate gyrus was obtained through the repetitive stimulation of the angular bundle and maximal dentate gyrus activation latency, duration and post-stimulus afterdischarge duration were evaluated.ResultsEither Lamotrigine (10 mg kg-1) or 7-nitroindazole (75 mg kg-1) i.p. administration had an anticonvulsant effect, significantly reducing the number of animals responding to angular bundle stimulation. On the contrary, i.p. injection of L-arginine (1 g kg-1) induced an aggravation of the epileptiform phenomena, demonstrated by the significant augmentation of the duration of both maximal dentate activation and afterdischarge. Furthermore, the injection of lamotrigine and 7-nitroindazole in combination significantly increased the anticonvulsant effects induced by the same drugs separately, either reducing the number of responding animals or decreasing both maximal dentate gyrus activation and afterdischarge durations. On the contrary, the combined treatment with L-arginine and lamotrigine did not modify the maximal dentate gyrus activation parameters suggesting an adversative effect of L-arginine-increased nitric oxide levels on the lamotrigine-induced anticonvulsant action.ConclusionThe present results indicate that the nitrergic neurotransmission exerts a significant modulatory role in the control of the development of paroxystic phenomena in the maximal dentate gyrus activation model of epilepsy. Finally, our data suggest a functional relationship between the nitric oxide system and the anticonvulsant effect of lamotrigine which could be enhanced by reducing nitric oxide levels and, conversely, dampened by an increased nitrergic activity.
Highlights
The effects induced by administering the anticonvulsant lamotrigine, the preferential inhibitor of neuronal nitric oxide synthase 7-nitroindazole and the precursor of Nitric oxide (NO) synthesis Larginine, alone or in combination, on an experimental model of partial complex seizures were studied in urethane anaesthetized rats
Nitric oxide (NO) is a gaseous messenger synthesised from the oxidation of L-arginine by three different isoforms of NO synthase (NOS): the neuronal and endothelial isoforms are calcium activated, on the contrary the inducible isoform is activated by a calcium independent enzyme
Once the maximal dentate gyrus activation (MDA) was elicited, the values for all the following parameters of the MDA were analysed: i) the onset of the MDA was considered as the time from the beginning of angular bundle (AB) stimulation to the midpoint of the shift of the DC potential; ii) the total duration of the MDA was measured from the midpoint of the shift of DC the potential to the point at which the evoked paroxystic activity abruptly ceased; iii) the afterdischarge (AD) duration was measured from the end of AB stimulation to the end of the epileptiform activity (Figure 1A)
Summary
The effects induced by administering the anticonvulsant lamotrigine, the preferential inhibitor of neuronal nitric oxide synthase 7-nitroindazole and the precursor of NO synthesis Larginine, alone or in combination, on an experimental model of partial complex seizures (maximal dentate gyrus activation) were studied in urethane anaesthetized rats. Several experimental researches have demonstrated the functional involvement of NO in both pro-convulsant and anticonvulsant phenomena but no definitive conclusions are still available [5,6]. Such heterogeneity of the responses to the pharmacological manipulation of the NO system could be related to the different models of experimental epilepsy used [7]. LTG is able to reduce NO release but, in the mouse model of maximal electroshock seizure, the combination between 7-NI and LTG was neutral in relation to a possible increase of the anticonvulsant effect [22,23]. It has been proposed that NO-mediated mechanisms are involved in the anticonvulsant efficacy of LTG [24]
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