Nucleolar enlargement, nuclear eccentricity and altered cell body immunostaining characteristics of large-sized sensory neurons following treatment of rats with paclitaxel.

Paclitaxel-induced sensory neuropathy is a problematic side-effect of cancer chemotherapy. Previous studies in rodents have shown paclitaxel treatment to have many effects on different parts of the peripheral nervous system, but those responsible for its bothersome clinical side-effects are still unclear. In the current study, we sought to obtain information about the involvement of sensory neurons in paclitaxel neurotoxicity at the level of the dorsal root ganglion. Rats were treated with a clinically relevant dose of paclitaxel (87.5mg/m(2) weekly for a total of nine doses) to induce a sensory neuropathy; then their L5 dorsal root ganglia were studied by morphometry and immunohistochemistry. Paclitaxel treatment was generally well tolerated, and slowed conduction velocity and prolonged conduction latencies in the peripheral sensory nerves without altering conduction in the central or motor pathways of the H-reflex arc. In the L5 dorsal root ganglion, nucleolus size and the number of neurons with eccentric nuclei were increased only in a subpopulation of dorsal root ganglion neurons with cell body cross-sectional areas greater than 1750 microm(2), which made up less than 10% of the total population. Paclitaxel treatment increased immunohistochemical staining for activating transcription factor-3 (ATF-3), c-Jun and neuropeptide Y (NPY) but only in a small percentage of neuronal cell bodies and mainly in those with large cell bodies. In conclusion, we have demonstrated that nucleolar enlargement, nuclear eccentricity, ATF-3, c-Jun and NPY are neuronal markers of paclitaxel-induced sensory neuropathy, however, these axotomy-like cell body reactions are infrequent and occur in mainly large-sized sensory neurons.

Oxaliplatin causes selective atrophy of a subpopulation of dorsal root ganglion neurons without inducing cell loss.

Peripheral neuropathy is induced by multiple doses of oxaliplatin and interferes with the clinical utility of the drug in patients with colorectal cancer. In this study, we sought to determine whether cell loss or selective neuronal damage was the basis for the peripheral neuropathy caused by oxaliplatin. Adult female rats were given 1.85 mg/kg oxaliplatin twice per week for 8 weeks. Nerve conduction and L5 dorsal root ganglia (DRG) were studied 1 week after the completion of all treatment. No mortality occurred during oxaliplatin treatment, but the rate of body weight gain was reduced compared to age-matched vehicle-treated controls. Oxaliplatin slowed conduction velocity and delayed conduction times in peripheral sensory nerves, without affecting central or motor nerve conduction. In L5 DRG, total numbers of neurons were unchanged by oxaliplatin, but there were significant reductions in neuronal size distribution, ganglion volume, average cell size and the relative frequency of large cells. In addition, the relative frequency of small DRG cells was increased by oxaliplatin. Oxaliplatin significantly altered the size distribution and average cell body area of the predominantly large parvalbumin-immunoreactive DRG neurons without affecting the frequency of parvalbumin staining. On the contrary, neither the staining frequency nor the size distribution of the predominantly small substance P-immunoreactive DRG neurons was changed by oxaliplatin. In conclusion, oxaliplatin causes selective atrophy of a subpopulation of DRG neurons with predominantly large parvalbumin-expressing cells without inducing neuronal loss. Because DRG cell body size and axonal conduction velocity are positively correlated, neuronal atrophy may be the morphological basis for the development of decreased sensory nerve conduction velocity that characterizes oxaliplatin-induced peripheral neuropathy.

Paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons in vivo reducing oxaliplatin toxicity.

Paclitaxel and oxaliplatin are promising drugs for combination trials but both induce peripheral neurotoxicity. To investigate this toxicity, 10-week-old female Wistar rats were given single intraperitoneal doses of paclitaxel and oxaliplatin, alone or in combination. Neurotoxicity was assessed by L5 dorsal root ganglion morphometry and H-reflex-related sensory nerve conduction velocity. Platinum concentrations in dorsal root ganglia and plasma were measured by inductively coupled plasma mass spectrometry. Dorsal root ganglion nucleolus size was significantly increased following single doses of paclitaxel of 10 and 20 mg kg(-1) at 24 h and 6 days (P<0.02). In contrast, dorsal root ganglion nucleolus size was significantly decreased following single doses of oxaliplatin ranging from 3 to 30 mg kg(-1) at time points ranging from 2 h to 14 days. Sensory nerve conduction velocity was altered after a single dose of oxaliplatin but not after paclitaxel. In combination with oxaliplatin, paclitaxel did not alter the plasma pharmacokinetics or dorsal root ganglion accumulation of oxaliplatin-derived platinum. However, prior paclitaxel inhibited oxaliplatin-induced reductions of dorsal root ganglion nucleolar diameter (P<0.02). Sensory nerve conduction velocity was reduced after oxaliplatin alone (P&<0.05) but unchanged when paclitaxel was given before oxaliplatin. In conclusion, paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons after pharmacologically relevant doses in vivo and reduces oxaliplatin nucleolar damage and neurotoxicity.