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Updated: Mar 26, 2026
Nerve Excitability Assessment in Chemotherapy-induced Neurotoxicity
Published on: April 26, 2012
Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy
Maria Domenica Sanna1, Carla Ghelardini, Nicoletta Galeotti
1Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Florence, Italy.
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 RNA-binding 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.
Insights
Oxaliplatin treatment alters key neuronal proteins, impacting structural changes in the central nervous system and contributing to chemotherapy-induced neurotoxicity.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Oxaliplatin is a vital chemotherapy drug for solid tumors.
- Neurotoxicity is a primary dose-limiting side effect of oxaliplatin.
- Understanding oxaliplatin's neuronal effects is crucial for managing toxicity.
Purpose of the Study:
- To investigate the structural neuronal changes induced by oxaliplatin.
- To examine protein expression alterations in the spinal cord and brain.
- To correlate these changes with oxaliplatin-induced neurotoxicity and thermal hyperalgesia.
Main Methods:
- Western blotting was used to analyze protein expression in mouse cortex, thalamus, PAG, and spinal cord.
- Thermal nociception was assessed using the hot plate test.
- Protein kinase C (PKC) inhibitor was administered to evaluate its role.
Main Results:
- Oxaliplatin reduced levels of GAP43 and HuD in the cortex and spinal cord.
- Decreased neurofilament-H (NfH) phosphorylation was observed during peak neurotoxicity, with subsequent increases indicating regeneration.
- Upregulation of PKCγ in the thalamus and PAG was linked to thermal hyperalgesia.
Conclusions:
- Oxaliplatin-induced neurotoxicity is associated with significant changes in regulatory and structural neuronal proteins.
- These findings highlight a direct correlation between central nervous system structural alterations and chemotherapy-induced neurotoxicity.
- Targeting PKC may offer therapeutic strategies for managing oxaliplatin neurotoxicity.
