Oxaliplatin-Induced Loss of Phosphorylated Heavy Neurofilament Subunit Neuronal Immunoreactivity in Rat Drg Tissue

Abstract

BackgroundOxaliplatin and related chemotherapeutic drugs cause painful chronic peripheral neuropathies in cancer patients. We investigated changes in neuronal size profiles and neurofilament immunoreactivity in L5 dorsal root ganglion (DRG) tissue of adult female Wistar rats after multiple-dose treatment with oxaliplatin, cisplatin, carboplatin or paclitaxel.ResultsAfter treatment with oxaliplatin, phosphorylated neurofilament heavy subunit (pNF-H) immunoreactivity was reduced in neuronal cell bodies, but unchanged in nerve fibres, of the L5 DRG. Morphometric analysis confirmed significant changes in the number (-75%; P < 0.0002) and size (-45%; P < 0.0001) of pNF-H-immunoreactive neurons after oxaliplatin treatment. pNF-H-immunoreactive neurons had overlapping size profiles and co-localisation with neurons displaying cell body immunoreactivity for parvalbumin, non-phospho-specific neurofilament medium subunit (NF-M) and non-phospho-specific neurofilament heavy subunit (NF-H), in control DRG. However, there were no significant changes in the numbers of neurons with immunoreactivity for parvalbumin (4.6%, P = 0.82), NF-M (-1%, P = 0.96) or NF-H (0%; P = 0.93) after oxaliplatin treatment, although the sizes of parvalbumin (-29%, P = 0.047), NF-M (-11%, P = 0.038) and NF-H (-28%; P = 0.0033) immunoreactive neurons were reduced. In an independent comparison of different chemotherapeutic agents, the number of pNF-H-immunoreactive neurons was significantly altered by oxaliplatin (-77.2%; P < 0.0001) and cisplatin (-35.2%; P = 0.03) but not by carboplatin or paclitaxel, and their mean cell body area was significantly changed by oxaliplatin (-31.1%; P = 0.008) but not by cisplatin, carboplatin or paclitaxel.ConclusionThis study has demonstrated a specific pattern of loss of pNF-H immunoreactivity in rat DRG tissue that corresponds with the relative neurotoxicity of oxaliplatin, cisplatin and carboplatin. Loss of pNF-H may be mechanistically linked to oxaliplatin-induced neuronal atrophy, and serves as a readily measureable endpoint of its neurotoxicity in the rat model.

Multimodal Assessment of Painful Peripheral Neuropathy Induced by Chronic Oxaliplatin-Based Chemotherapy in Mice

“…Following the finding that oxaliplatin induced a decrease in NCV and action potential amplitude; we examined the morphology of DRG neurons and sciatic nerve at the light and electron microscope levels. Our findings that the diameter of DRG cell bodies is reduced after chronic oxaliplatin treatment is also similar to findings in the rat [7,34,43,45,46], which are suggestive of neuronal atrophy that could be related to a decrease in phosphorylated neurofilament [45]. Finally, our morphological examination of DRGs and sciatic nerves revealed that many of the neurons were multinucleolated, that the nucleoli were eccentric and that rare nerve fibers presented mild signs of axonopathy.…”

Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy

“…Increasing evidence indicates that the cytoskeleton is one of the most important targets of neurotoxic agents. Many studies have shown that changes occur in Nf proteins during development in response to neurotoxicity in vivo [19] and neurotoxic agents were correlated with decreased neurite growth in vitro [20] . Previous studies have demonstrated a specific pattern of loss of pNfH immunoreactivity in rat DRG and nerve tissue after oxaliplatin administration [21] .…”

Plasticity of dorsal root ganglion neurons in a rat model of post-infectious gut dysfunction: potential implication of nerve growth factor

“…According to their size, cells were classified as: small (cross-sectional area £500 mm 2 ), medium (500-1000 mm 2 ), large (1000-1500 mm2), and very large (>1500 mm 2 ) [14,15].…”