Inhibition of glial Na+ and K+ currents by tamoxifen

Tamoxifen (tmx) is a non-steroidal triphenylethylene derivative that is predominantly known as a competitive antagonist at the estrogen receptor and is used in the treatment of boast cancer. Recent studies suggest that tamoxifen is also beneficial in the treatment of brain metastases and primary brain tumors. Tmx accumulates in brain and its concentration can be up to 46-fold higher than in serum. Therefore, astrocytes may be exposed to tmx in vivo. We use the whole-cell patch-clamp technique to examine the effects of tmx on voltage-dependent cation currents in rat cortical cultures. Using biophysical and pharmacological methods, we isolate sustained and transient outward potassium currents (I-KS and I-KT, respectively), inwardly rectifying potassium currents (I-KIR), and transient inward sodium currents (I-Na). We show that that TTX-sensitive I-Na is completely inhibited by 10 muM tmx within 5 min. Similarly, tmx blocks I-KS but does not inhibit I-KT or I-KIR at these concentrations. Tmx effects are irreversible with 10 min wash. Interestingly, the currents sensitive to tmx are important in growth control of glial cells (MacFarlane & Sontheimer, 1997). Therefore, we examine cytotoxic and proliferative effects of tmx. Tmx (10 muM) is not cytotoxic as judged by trypan blue exclusion. However, incubation with tmx significantly reduces cell proliferation as examined by (3)[H]-thymidine uptake.