Cyclosporine induces epileptiform activity in an in vitro seizure model

Purpose: Cyclosporine (CSA) toxicity represents a common cause of seizures in transplant patients, but the specific mechanisms by which CSA induces se izures are unknown. Although CSA may promote seizure activity by various me tabolic, toxic, vascular, or structural mechanisms, CSA also has been hypot hesized to modulate neuronal excitability directly. The objective of this s tudy was to determine if CSA exerts direct epileptogenic actions on neurons in an in vitro seizure model. Methods: Combined hippocampal-entorhinal cortex slices from juvenile rats w ere exposed directly to artificial cerebrospinal fluid (ACSF) containing ei ther (a) 1.0 mM magnesium sulfate (control), (b) 1.0 mM sodium sulfate (low -magnesium), or(c) 1.0 mM magnesium sulfate + CSA (1,000-10,000 ng/ml). Spo ntaneous and evoked extracellular field potentials were recorded simultaneo usly from the dentate gyrus (DG) and CA3 hippocampal regions. Evoked synapt ic responses were elicited by stimulation of the entorhinal cortex/perforan t pathway. Results: CSA elicited spontaneous or stimulation-induced epileptiform activ ity in the DG or CA3 region of similar to 40% of slices, consisting of brie f repetitive "interictal" discharges or prolonged stereotypical "ictal" dis charges. Mean latency to epileptiform activity was similar to 100 min after onset of CSA application. The interictal discharges were inhibited by the non-NMDA antagonist, NBQX. Similar epileptiform activity was observed in lo w-magnesium ACSF without CSA. In control ACSF alone, epileptiform activity was not seen, except for rare spontaneous potentials in the DG. Conclusions: Direct effects of CSA on neuronal excitability and synaptic tr ansmission may contribute to seizures seen in clinical CSA neurotoxicity.