Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents.

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (I_h) and membrane electroporation-induced current (I_MEP). OXAL increased the amplitude or activation rate constant of I_h in a concentration-dependent manner with effective EC₅₀ or K_D values of 3.2 or 6.4 μM, respectively, in pituitary GH₃ cells. The stimulation by this agent of I_h could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 μM) resulted in an approximately 11 mV rightward shift in I_h activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of I_MEP elicited by large hyperpolarization in GH₃ cells with an EC₅₀ value of 1.3 μM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of I_MEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (I_MEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated I_h remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase I_MEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of I_h and I_MEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur.