Novel actions of oxazolidinones: in vitro screening of a triazolyloxazolidinone for anticonvulsant activity

Abstract

Objective: To test the hypothesis that a triazolyloxazolidinone (PH084) has anticonvulsant activity by examining its effects on in vitro seizure models in the rat hippocampus.

Materials and methods: Whole-cell synaptic currents, action potentials and extracellular population spikes (PS) were recorded in the cell body area of rat hippocampal CA1 region in acutely prepared slices. Chemical [picrotoxin (100 µM) and zero magnesium] and electrical seizures were induced and the effect of PH084 (10 µM) was tested on cellular responses, multiple spikes and spontaneous bursting frequencies.

Results: PH084 depressed evoked excitatory postsynaptic currents, action potential firing frequency and PS amplitude. All of these responses did not recover to baseline after 15-20 min washout of PH084. Perfusion with zero magnesium ion (Mg(2+))-containing buffer converted a single PS to multiple PS (mPS) accompanied by spontaneous burst. PH084 suppressed the mPS and the spontaneous burst frequency and it also suppressed the picrotoxin-induced mPS number. However, it did not affect the frequency of stimulus train-induced after discharge or bursts. Furthermore, 8-10 min pretreatment with PH084 did not affect the ability of zero Mg(2+) buffer, picrotoxin or stimulus train to induce epileptiform activity.

Conclusions: Thus, while PH084 may have potential for anticonvulsant activity against chemically induced seizures, it has little or no potential against electrically induced seizures or in preventing epileptiform discharge.

Fig. 1

PH084 depresses evoked EPSC amplitude and action potential firing rate recording in CA1 pyramidal cells. In this figure and in all other figures, * indicates statistical significance at p ≤ 0.05 compared to control.

Fig. 2

PH084 irreversibly depresses PS recorded in the cell body layer of the hippocampal CA1 region.

Fig. 3

PH084 depresses zero Mg^2s+-induced epileptiform activity (mPS and SBs) that is eliminated by TTX.

Fig. 4

PH084 does not affect stimulus train-induced ADs and SBs.