Abstracts

RATIONALE: Cyclosporin A (CSA) is an important immunosuppressant, but it has serious side effects, including seizures. This proconvulsant potential is exacerbated by certain drugs. It is important to identify drugs that [arrowup] or [arrowdown] its proconvulsant potential, especially drugs commonly given to patients on CSA. For example, opiates may be given for pain control after transplantation surgery. Seizures have been observed in patients receiving both CSA and opiates, but it is not clear if opiates generally promote, or suppress, CSA-associated seizures. Either outcome may be possible, given the reported pro- and anti-convulsant effects of opiates.
METHODS: An [italic]in vitro[/italic] hippocampal slice model of seizures was used to assess the actions and interactions between CSA and opiates. In slices from juvenile (P14-21) rats, electrographic seizures (EGSs) were evoked in area CA3 using stimulus trains (60 Hz, 2 s, 400-600 [mu]A) given at 10 min. intervals. Drug effects were measured on extracellularly recorded epileptiform activity, including EGS duration (in sec.), EGS intensity (in [pound] of spikes/EGS) and interictal-like spontaneous epileptiform bursts (sEBs) (in [pound] of sEB events per 10-min. inter-train interval).
RESULTS: In control ACSF, parameters of epileptiform activity were: EGS duration (31.4[plusminus]1.50), intensity (113.3[plusminus]15.5), and sEBs (16.4[plusminus]12.9) (n=13). Alone, CSA (3[mu]M) had significant (*p[lt]0.05) effects: it modestly increased EGS duration (35.5[plusminus]1.4*), intensity (133[plusminus]17.9*), and sEBs (63.6[plusminus]35.8*) (n=13). Opioid effects were complex. Alone, fentanyl (FENT; 50 ng/ml) reduced EGS duration (23.1[plusminus]2.4*), but not intensity (85.9[plusminus]8.1), yet increased sEBs (132.0[plusminus]14.0*)(n=5). Effects of the specific [mu] (OP3) receptor agonist peptide [D-Ala2, N-Me-Phe4, Gly-ol]-enkephalin (DAMGO) (1 [mu]M) resembled FENT generally with respect to EGS duration (12.7[plusminus]2.8), intensity (87.3[plusminus]11.1), and sEBs (64.2[plusminus]23.0)(n=5). When applied together (FENT+CSA), FENT reversed (or over-rode) the effects of CSA on EGSs, for FENT+CSA reduced EGS duration (24.9[plusminus]1.9*) and intensity (90.3[plusminus]16.5*)(n=4). In contrast, FENT+CSA greatly increased sEB activity (218.0[plusminus]100.5*; n=4) compared to FENT or CSA alone. This suggests FENT and CSA may interact synergistically.
CONCLUSIONS: These results suggest that CSA and FENT may have complex interactions when used in combination [italic]in vivo[/italic]- and such interactions may not be easy to predict based on the effects of each drug used alone. Thus, these [italic]in vitro[/italic] findings may help to predict pro- and anticonvulsant interactions that may arise in clinical settings.
Support: Catholic Univeristy Medical Center, Seoul (B-J.C.); Dept. Veterans Aff.(S.C. & W.A.W.); NIH DA6735(Q.L. & D.V.L.).