Cannabinoid-‐mediated modulation of hippocampal hyperexcitability: focus on the interplay with nitrergic system in different rat models of temporal lobe epilepsy.

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Temporal lobe epilepsy (TLE) is the most common type of partial complex seizure in adulthood [1]. Within the framework of hyperexcitability, growing interest has risen on the impact of cannabinoids on the control of paroxysmal phenomena [2], despite their reputation as psychotropic substances with addictive properties [3; 4]. In this regard, it was reported that the on-demand production of endocannabinoids from over-activated postsynaptic cells inhibits neurotransmitter release, hence protecting against excitotoxicity in the hippocampus [5; 6]. Nonetheless, the potential anticonvulsant action of cannabinoids has not been fully addressed. Indeed, CB-mediated effects in animal models are attributed not only to the functional involvement of the classical CB receptors-dependent signalling [7; 8], but also to the interaction with further synaptic processes concerning modulatory messengers. Among these, nitric oxide (NO) has caught our attention since it apparently acts as a mediator for cannabinoid effects [9; 10]. In the current study, we focused on two distinct rat models of TLE, the Maximal Dentate Activation and the Pilocarpine-induced acute seizures, providing electrophysiological and behavioural data on cannabinoid and nitrergic system interplay. We evaluated the antiepileptic effects of WIN 55,212-2 (WIN), a CB agonist, and of 7-Nitroindazole (7NI), a preferential inhibitor of neuronal NO synthase (nNOS), at different doses, alone and in combination. MDA study showed that these drugs protected animals from electrically-induced epileptiform discharges. In pilocarpine model, a dose-related activity of 7NI and WIN: a) decreased the behavioural scoring, used to describe the severity of chemically-induced acute seizures; b) affected latency of the onset of acute convulsions; c) dampened mortality rate. Interestingly, the combination of the treatments brought to light that individually ineffective doses of WIN turn into effective when nNOS activity is pharmacologically inhibited in both experimental conditions. Further MDA studies were conducted with a view to explore the pathway downstream NO. To achieve this, we modulated the activity of NO-dependent soluble Guanylate cyclase (sGC), a cGMP-synthase enzyme, which is the main target of NO signaling. We exploited ODQ, a NO-dependent-sGC inhibitor, to evaluate its effect in co-administration with WIN. Results obtained suggested a possible involvement of cGMP pathway in the crosstalk between CB and NO. Taken all these into consideration, our findings suggest a putative antagonism between CB-activated pathway and NO signalling in the context of neuronal hyperexcitability and contribute to elucidate possible synaptic processes underlying neuroprotective properties of cannabinoids, with a view to better integrate antiepileptic therapy.
Lingua originaleEnglish
Numero di pagine0
Stato di pubblicazionePublished - 2015

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