AN ELECTROPHYSIOLOGICAL INVESTIGATION OF THE EFFECTS OF CISPLATIN ANDTHE PROTECTIVE ACTIONS OF DEXAMETHASONE ON CULTURED DORSAL-ROOT GANGLION NEURONS FROM NEONATAL RATS

In this study we have investigated the acute and chronic effects of ci splatin on whole cell currents in cultured dorsal root ganglion neuron es. Consistent with effects on action potentials measured under curren t clamp, acute (5 min) application of cisplatin (5 mu M) attenuated vo ltage-activated potassium, and mixed cation currents by approximately 50% in both cases. Chronic treatment (5-7 days) of cultured neurones w ith 5 mu M cisplatin also resulted in greatly reduced voltage-activate d potassium currents (by 50%) and calcium currents (by 60%) compared t o events recorded from neurones not treated with cisplatin. In contras t, the amplitude of inward cation current activated by hyperpolarizati on was doubled by 5-12 days treatment with cisplatin. Studies on actio n potential after-depolarizations and calcium-activated chloride curre nts suggest that cisplatin disturbs calcium homeostatic mechanisms. Th ese 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 mu M) produced transient depolarizations and burs ts of action potentials, after 5 minutes application it had no effect on membrane potential, input resistance, or the properties of action p otentials evoked by depolarizing current commands. Compared to cells e xposed to cisplatin alone, combined treatment of cisplatin and dexamet hasone significantly improved survival of dorsal root ganglion neurone s in culture by 20%. Dexamethasone also showed signs of protecting neu rones from cisplatin by improving membrane potentials and action poten tial thresholds. In conclusion, cisplatin reduces the viability of dor sal root ganglion neurones in culture and alters their electrophysiolo gical properties. Evidence suggests that dexamethasone has some protec tive properties against the neurotoxic actions of cisplatin.