Inhibition of glial Na+ and K+ currents by tamoxifen

Tamoxifen (tmx) is a non-steroidal triphenylethylene derivative that is pre dominantly known as a competitive antagonist at the estrogen receptor and i s used in the treatment of boast cancer. Recent studies suggest that tamoxi fen is also beneficial in the treatment of brain metastases and primary bra in tumors. Tmx accumulates in brain and its concentration can be up to 46-f old higher than in serum. Therefore, astrocytes may be exposed to tmx in vi vo. We use the whole-cell patch-clamp technique to examine the effects of tmx o n voltage-dependent cation currents in rat cortical cultures. Using biophys ical and pharmacological methods, we isolate sustained and transient outwar d potassium currents (I-KS and I-KT, respectively), inwardly rectifying pot assium currents (I-KIR), and transient inward sodium currents (I-Na). We sh ow that that TTX-sensitive I-Na is completely inhibited by 10 muM tmx withi n 5 min. Similarly, tmx blocks I-KS but does not inhibit I-KT or I-KIR at t hese concentrations. Tmx effects are irreversible with 10 min wash. Interestingly, the currents sensitive to tmx are important in growth contro l of glial cells (MacFarlane & Sontheimer, 1997). Therefore, we examine cyt otoxic and proliferative effects of tmx. Tmx (10 muM) is not cytotoxic as j udged by trypan blue exclusion. However, incubation with tmx significantly reduces cell proliferation as examined by (3)[H]-thymidine uptake.