Correlation between organic cation transporter expression in rat dorsal root ganglia neurons and cisplatin-induced peripheral neurotoxicity

Organic cation transporters (OCTs) are critical in drug absorption, targeting, and disposition. It has become increasingly clear the role of these transporters in key tissues responsible for drug absorption and disposition: kidney, liver and intestine. However, only limited information is available regarding their distribution and activity in nervous system. Cisplatin (CDDP), a widely used chemotherapeutic agent for the treatment of several solid tumors induces a severe and dose-limiting sensory neuropathy, due to damage of the primary sensory neurons of the dorsal root ganglia (DRG) where it forms DNA adducts. This study was aimed to investigate (1) the expression of different OCTs (OCT-1, OCT-2, OCTN-1 and OCTN-2) in DRG neurons and (2) their putative role in CDDP-induced peripheral neurotoxicity. OCTs expression in rat DRG was studied by TaqMan Real Time PCR in control and CDDP treated (2 mg/Kg i.p. 2qw x4) Wistar rats. It was demonstrated that CDDP administration reduced OCT2 mRNA levels with respect to the control. To examine the functional role of OCT-2, the correlation existing between the neurophysiologic/morphometric parameters and the OCT-2 mRNA levels were studied. This analysis evidenced that the reduction of OCT-2 expression correlated with the decrease of NCV and with the reduction of soma, nucleus and nucleolus size in treated animals. To obtain mechanistic information about the role of OCT-2 in CDDP neurotoxicity a pilot in vivo study was performed. Female Wistar rats were randomized in 3 different groups and treated as follows: CDDP 2 mg/Kg i.p. 2qw x4; CDDP 2 mg/Kg i.p. 2qw x4 + cimetidine (CMT) 60 mg/kg os daily for 4 weeks; un-treated control rats. The OCT-2 inhibitor CMT could not revert the CDDP-induced NVC impairment, although it significantly ameliorated morphometric parameters. An in vitro model of DRG neurons obtained from embryonic rats E15 was used.to confirm a partial neuroprotective effect of CMT. Nerve growth factor (NGF) differentiated neurons were exposed to CDDP alone or in combination with CMT. After 24 and 48 hours of co-treatment with CDDP and CMT 100 microM a significant increase of neuronal survival was observed with respect to CDDP treated cells. Our data suggest that rOCT2 could be involved in CDDP uptake in DRG neurons. The hypothesis is that CDDP treatment could determine a decrease in rOCT2 expression as a neuronal defense response against subsequent exposure and neuronal uptake of CDDP. Supported in part by an unrestricted research grant from the “Fondazione Banca del Monte di Lombardia”