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

Background: Oxaliplatin is a platinum compound widely used in the treatment of some solid tumors. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug. This study examined the structural neuronal effects of oxaliplatin treatment in spinal and supraspinal levels. Methods: Protein expression was investigated in the mouse cortex, thalamus, periaqueductal grey (PAG) matter and spinal cord (SC) by Western blotting. Thermal nociception was assessed by the hot plate test. Results: Results indicate a reduction in the levels of growth associated protein-43 (GAP43) in the cortex and SC areas at the end of thermal hyperalgesic response, while a decrease in neurofilament-H (NfH) phosphorylation was observed in the SC on day 21 when the pain-related manifestation reaches the neurotoxic peak. Counteracting phosphorylated NfH content increases in the SC and cortex regions at day 28 as a result of the beginning of neuro-regeneration process. We also revealed that the levels of HuD, a neuronal-specific RNAbinding protein, decreased, demonstrating the same temporal and regional expression pattern of GAP43. Oxaliplatin chronic treatment induced a region-specific upregulation of γ isoform of protein kinase C (PKC) within thalamus and PAG, and the administration of a PKC inhibitor suggests that PKC activity in these brain regions must be required to maintain the thermal hyperalgesic state. Conclusions: These results suggest that changes in the protein levels of the regulatory and structural proteins are due to oxaliplatin-induced neurotoxicity and imply that there is a direct link between structural changes in the central nervous system and chemotherapy-induced neurotoxicity.