Abstract
It this study we have investigated the acute and chronic effects of cisplatin on whole cell currents in cultured dorsal root ganglion neurones. Consistent with effects on action potentials measured under current clamp, acute (5 min) application of cisplatin (5 μM) attenuated voltage-activated potassium, and mixed cation currents by approximately 50% in both cases. Chronic treatment (5–7 days) of cultured neurones with 5 μM cisplatin also resulted in greatly reduced voltage-activated potassium currents (by 50%) and calcium currents (by 60%) compared to events recorded from neurones not treated with cisplatin. In contrast, the amplitude of inward cation current activated by hyperpolarization was doubled by 5–12 days treatment with cisplatin. Studies on action potential after-depolarizations and calcium-activated chloride currents suggest that cisplatin disturbs calcium homeostatic mechanisms. These observations may account for anode break spike excitation and the low efficiency with which cells buffer intracellular calcium following cisplatin treatment.
Dexamethasone has been found to enhance the anti-emetic effects of 5-HT3 receptor antagonists in patients treated with cisplatin. For this reason the actions of dexamethasone were studied in combination with cisplatin treatment. Although acute application of dexamethasone (1–10 μM) produced transient depolarizations and bursts of action potentials, after 5 minutes application it had no effect on membrane potential, input resistance, or the properties of action potentials evoked by depolarizing current commands. Compared to cells exposed to cisplatin alone, combined treatment of cisplatin and dexamethasone significantly improved survival of dorsal root ganglion neurones in culture by 20%. Dexamethasone also showed signs of protecting neurones from cisplatin by improving membrane potentials and action potential thresholds. In conclusion, cisplatin reduces the viability of dorsal root ganglion neurones in culture and alters their electrophysiological properties. Evidence suggests that dexamethasone has some protective properties against the neurotoxic actions of cisplatin.
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Scott, R.H., Woods, A.J., Lacey, M.J. et al. An electrophysiological investigation of the effects of cisplatin and the protective actions of dexamethasone on cultured dorsal root ganglion neurones from neonatal rats. Naunyn-Schmiedeberg's Arch Pharmacol 352, 247–255 (1995). https://doi.org/10.1007/BF00168554
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DOI: https://doi.org/10.1007/BF00168554