Enhanced NMDA(R)-dependent epileptiform activity is controlled by oxidizing agents in a chronic model of temporal lobe epilepsy

1. Graded N-methyl-D-aspartate receptor (NMDA(R))-dependent epileptiform discharges were recorded from ex vivo hippocampal slices obtained from rats injected a week earlier with an intracerebroventricular dose of kainic acid. Intracellular recordings from pyramidal cells of the CA1 area showed that glutamate NMDA(R) actively participated in synaptic transmission, even at resting membrane potential. When NMDA(R) were pharmacologically isolated, graded burst discharges could still be evoked. 2. The oxidizing reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB, 200 mu M, 15 min) suppressed the late part of the epileptiform burst that did not recover after wash but could be reinstated by the reducing agent tris(2-carboxyethyl)phosphine (TCEP, 200 mu M, 15 min) and again abolished with the NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-APV). 3. Pharmacologically isolated NMDAR-mediated responses were: decreased by DTNB (56 +/- 10%, mean +/- SD, n = 6), an effect reversed by TCEP. 4. When only the fast glutamatergic synaptic component was blocked, NMDA-dependent excitatory postsynaptic potentials (EPSPs) could be evoked despite the presence of underlying fast and slow inhibitory postsynaptic potentials (IPSPs). DTNB decreased EPSPs to 48 +/- 12% (n = 5) of control. 5. Since a decrease of the NMDA(R)-mediated response by +/-50% is sufficient to suppress the late pare of the burst, we suggest that epileptiform activity can be controlled by manipulation of the redox sites of NMDA(R). Our observations raise the possibility of developing new anticonvulsant drugs that would spare alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-R (AMPA(R))-mediated synaptic responses and decrease NMDA(R)-mediated synaptic transmission without blocking it completely.