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Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of
Wei-Ting Chang1,2,3, Zi-Han Gao4, Shih-Wei Li4
1Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan.
Abstract:
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 (Ih) and membrane electroporation-induced current (IMEP). OXAL increased the amplitude or activation rate constant of Ih in a concentration-dependent manner with effective EC50 or KD values of 3.2 or 6.4 μM, respectively, in pituitary GH3 cells. The stimulation by this agent of Ih 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 Ih 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 IMEP 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 IMEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (IMEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated Ih remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase IMEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of Ih and IMEP 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.
Insights
Oxaliplatin (OXAL) increases neuronal membrane currents (Ih and IMEP) in a dose-dependent manner. This platinum-based anti-neoplastic agent may enhance neuronal excitability, potentially contributing to peripheral neuropathy.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Oxaliplatin (OXAL) is a platinum-based chemotherapy agent.
- Peripheral neuropathy is a known side effect of long-term Oxaliplatin administration.
- The precise mechanisms by which Oxaliplatin affects neuronal ion channels remain largely unknown.
Purpose of the Study:
- To investigate the effects of Oxaliplatin on hyperpolarization-activated cation current (Ih) and membrane electroporation-induced current (IMEP).
- To explore the interaction of Oxaliplatin with specific ion currents in pituitary cells and olfactory neurons.
- To elucidate potential mechanisms underlying Oxaliplatin-induced neurotoxicity.
Main Methods:
- Electrophysiological recordings in pituitary GH3 and R1220 cells, and Rolf B1.T olfactory sensory neurons.
- Concentration-dependent application of Oxaliplatin to measure changes in Ih and IMEP.
- Assessment of Oxaliplatin's effects on current-voltage relationships and voltage-dependent hysteresis.
Main Results:
- Oxaliplatin significantly increased the amplitude and activation rate of Ih in GH3 cells (EC50/KD: 3.2/6.4 μM), an effect partially reversible by ivabradine, protopine, or dexmedetomidine.
- Oxaliplatin also increased IMEP amplitude in GH3 cells (EC50: 1.3 μM) and olfactory neurons, an effect not attenuated by the same drugs.
- Oxaliplatin induced a rightward shift in Ih activation and altered voltage-dependent hysteresis and IMEP current-voltage relations.
Conclusions:
- Oxaliplatin enhances neuronal membrane currents, Ih and IMEP, suggesting increased neuronal excitability.
- These synergistic effects may contribute to the development of Oxaliplatin-induced peripheral neuropathy.
- Further in vivo studies are warranted to confirm these findings and their clinical implications.
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