Modulation of Voltage-Gated Ion Channels on SH-SY5Y Neuroblastoma by Non-ionic Surfactant, Cremophor EL

Abstract

Cremophor EL (CrEL) is a non-ionic surfactant widely used as a vehicle for insoluble drugs, including immunosuppressive and anticancer agents. Although CrEL has often been reported to induce sensory neuropathies, its action on voltage-gated ion channels remains unknown. We show here that CrEL modulates voltage-gated sodium current (INa) and potassium current (IK) of human neuroblastoma cells (SH-SY5Y). First, CrEL suppressed the amplitude of INa and that of IK. The suppression-concentration curve for INa was gradual but that for IK was steeper, indicating that INa remains incompletely blocked by high concentrations of CrEL, which greatly reduce IK. Thus, it is possible that CrEL paradoxically increases neuronal excitability at higher concentrations. Next, CrEL accelerated IK's inactivation process. The voltage-dependent inactivation of IK showed two time constants, τ(f) of 322±49 ms and τ(s) of 2925±184 ms, under the control condition. By applying 1000 ppm CrEL, three time constants-τ(u) of 23±2 ms, τ(f) of 196±19 ms, and τ(s) of 1396±127 ms-appeared in the inactivation process. This modified inactivation of IK probably disturbs the repolarizing phases of action potentials. These modulations of voltage-gated ion channels by CrEL may cause abnormal excitability involved in neuropathies.