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Objective The need for alternative pharmacologic strategies in treatment of epilepsies is pressing for about 30% of patients with epilepsy who do not experience satisfactory seizure control with present treatments. In temporal lobe epilepsy ( TLE) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of TLE patients. In this study we investigate purinergic modulation of drug-resistant seizure-like events ( SLEs) in human temporal cortex slices. Methods Layer V/ VI field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor SLEs induced by application of 8 mM [K+] and 50 μ m bicuculline. Results Activating A1 receptors with a specific agonist completely suppressed SLEs in 73% of human temporal cortex slices. In the remaining slices, incidence of SLEs was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A1 agonist, in slices insensitive to a high dose of carbamazepine (50 μ m). Also in these cases the A1 agonist was equally efficient. Moreover, ATP and adenosine blocked or modulated SLEs, an effect mediated not by P2 receptors but rather by adenosine A1 receptors. Significance Selective activation of A1 receptors mediates a strong anticonvulsant action in human neocortical slices from pharmacoresistant patients. We propose that our human slice model of seizure-like activity is a feasible option for future studies investigating new antiepileptic drug ( AED) candidates. [ABSTRACT FROM AUTHOR]

Purpose: Adenosine is considered an endogenous anticonvulsant. However, much less is known about the putative effects of its precursor, ATP, on epilepsy. Therefore, we tested whether ATP and its receptors are able to modulate epileptiform activity in the medial entorhinal cortex of the rat. Methods: Recurrent epileptiform discharges (REDs) were induced by elevating extracellular potassium concentration combined with application of bicuculline in brain slices from naive and pilocarpine-treated chronic epileptic rats. Field potentials were recorded from layer V/VI of the medial entorhinal cortex. Key Findings: REDs in slices from naive animals had a higher incidence and a shorter duration than in slices from chronic epileptic animals. Exogenous application of ATP reversibly reduced the incidence of REDs in naive and chronic epileptic slices via activation of adenosine A1 receptors without discernible P2 receptor effects. This effect was stronger in slices from chronic epileptic rats. In slices from naive rats, the P2X7 receptor antagonist A 740003 slightly but significantly reduced the amplitude of slow field potentials of REDs. In slices from chronic epileptic rats, none of the P2 receptor antagonists affected the parameters of REDs. Significance: Our results suggest that endogenously released ATP differentially modulates REDs by activation of A1 and P2X7 receptors. Although it has a minor proepileptic effect by direct activation of P2X7 receptors, its metabolite adenosine reduces the epileptiform activity via activation of A1 receptors. The exact effect of ATP on neural activity depends on the actual activity of ectonucleotidases and the expression level of the purinergic receptors, which both alter during epileptogenesis. In addition, our data suggest that P2X7 receptor antagonists have a minor antiepileptic effect. [ABSTRACT FROM AUTHOR]

The function of adenosine A2A receptors, localized at the enkephalin-containing GABAergic medium spiny neurons of the striatum, has been discussed controversially. Here we show that, in the absence of external Mg2+, the adenosine A2A receptor agonist CGS 21680 postsynaptically depressed the NMDA, but not the non-NMDA (AMPA/kainate) receptor-mediated fraction of the electrically evoked EPSCs in a subpopulation of striatal neurons. Current responses to locally applied NMDA but not AMPA were also inhibited by CGS 21680. However, in the presence of external Mg2+, the inhibition by CGS 21680 of the GABAA receptor-mediated IPSCs led to a depression of the EPSC/IPSC complexes. The current response to the locally applied GABAA receptor agonist muscimol was unaltered by CGS 21680. Whereas, the frequency of spontaneous (s)IPSCs was inhibited by CGS 21680, their amplitude was not changed. Hence, it is suggested that under these conditions the release rather than the postsynaptic effect of GABA was affected by CGS 21680. In conclusion, under Mg2+-free conditions, CGS 21680 appeared to postsynaptically inhibit the NMDA receptor-mediated component of the EPSC, while in the presence of external Mg2+ this effect turned into a presynaptic inhibition of the GABAA receptor-mediated IPSC. [Copyright &y& Elsevier]

The effects of the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5′-N-ethylcarboxamidoadenosine (CGS 21680) on currents mediated by excitatory amino acid receptors were examined in rat striatal brain slices. In a Mg2+-free superfusion medium, CGS 21680 decreased the amplitude of excitatory postsynaptic currents (EPSCs) in about 70% of striatal neurons. The inhibitory effect of CGS 21680 disappeared both in the presence of the adenosine A2A receptor antagonist 8-(3-chlorostyryl) caffeine and the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5). NMDA-induced currents were also depressed by CGS 21680 in a subset of striatal cells, whereas α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-induced currents were not affected. The results suggest that adenosine A2A receptor agonists inhibit the NMDA component of the EPSC. [Copyright &y& Elsevier]

Abstract: The present study was designed to investigate the role of extracellular ATP and its receptors on neuronal network activity. Gamma oscillations (30–50 Hz) were induced in the CA3 region of acute rat hippocampal slices by either acetylcholine (ACh) or kainic acid (KA). ATP reduced the power of KA-induced gamma oscillations exclusively by activation of adenosine receptors after its degradation to adenosine. In contrast, ATP suppressed ACh-induced oscillations through both adenosine and ATP receptors. Activation of adenosine receptors accounts for about 55%, activation of P2 receptors for ∼45% of suppression. Monitoring the ATP degradation by ATP biosensors revealed that bath-applied ATP reaches ∼300 times lower concentrations within the slice. P2 receptors were also activated by endogenous ATP since inhibition of ATP-hydrolyzing enzymes had an inhibitory effect on ACh-induced gamma oscillations. More specific antagonists revealed that ionotropic P2X2 and/or P2X4 receptors reduced the power of ACh-induced gamma oscillations whereas metabotropic P2Y1 receptor increased it. Intracellular recordings from CA3 pyramidal cells suggest that adenosine receptors reduce the spiking rate and the synchrony of action potentials during gamma oscillations whereas P2 receptors only modulate the firing rate of the cells. In conclusion, our results suggest that endogenously released ATP differentially modulates the power of ACh- or KA-induced gamma oscillations in the CA3 region of the hippocampus by interacting with P2X, P2Y and adenosine receptors. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’. [Copyright &y& Elsevier]