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

Abstract

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.

RNA-Binding Proteins HuB, HuC, and HuD are Distinctly Regulated in Dorsal Root Ganglia Neurons from STZ-Sensitive Compared to STZ-Resistant Diabetic Mice

“…It is very interesting to remark that, despite the lack of changes in the algesic profile of diabetic resistant mice, we reported significant Elavl gene and Hu protein expression changes in diabetic resistant mice compared to diabetic or control mice. Previous studies indicated HuD upregulation in thermal hyperalgesia [19,50,51,52] and our study brings evidence that HuD is downregulated in thermal hypoalgesia induced by the advanced diabetes status. Considering the role played by HuD upregulation in nerve regeneration upon lesion [21], a possible scenario in diabetes would be: (i) hyperalgesia (early phases of diabetes) is associated with HuD upregulation involved in nerve regeneration, (ii) hypoalgesia (late phases of diabetes) is associated with HuD downregulation, when its ability to regulate mRNA proteins involved in nerve recovery is overcome.…”

“…Considering previous studies that reported the role played by Hu proteins from DRG neurons in hyperalgesia [19,48,49,50,51,52], we analyzed the expression changes of Hu proteins in diabetic and diabetic resistant mice compared to control mice and correlated these data with algesic profile to radiant heat exposure. To detail, HuR contributes to hyperalgesia either associated with experimental autoimmune encephalomyelitis [48] or with inflammation (exposure to bradykinin and interleukin-1) where stabilized cyclooxygenase-2 mRNA [49].…”

“…To detail, HuR contributes to hyperalgesia either associated with experimental autoimmune encephalomyelitis [48] or with inflammation (exposure to bradykinin and interleukin-1) where stabilized cyclooxygenase-2 mRNA [49]. HuD is upregulated and contributes to pain hypersensitivity to mechanical and cold stimulation in antiretroviral-evoked painful neuropathy by regulating spinal ryanodine receptor-2 [50] or GAP43 [19,51] or contributes to thermal hot hyperalgesia in oxaliplatin-induced neuropathy by regulating GAP43 [52]. On the other hand, to the best of our knowledge, this is the first study documenting the role of Hu proteins in hypoalgesia associated with the diabetic condition, addressing the expression of Hu proteins in DRG neurons.…”

Post-chemotherapy neuropathy

“…The combination of a platinum salt and a taxane is the treatment of choice for ovarian epithelial tumors. In this context, chemotherapy-IPN is often an adverse event of the treatment which may limit its administration and a new treatment cycle, thus impacting patients' survival in case of recurrence, since neuropathy often lasts beyond the recurrence period 8 . Bortezomib is a proteasome inhibitor used to treat recently diagnosed or recurrent myeloma and mantle cells lymphoma.…”

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

“…In the study of Branca et al [127], oxaliplatin administration in vitro induced significant changes in the junctional and cytoskeletal apparatus of endothelial cells, and these alterations of BBB may be associated with higher concentrations of oxaliplatin in the brain and probably contribute to pain chronification. The study of Sanna et al shows that oxaliplatin administration induces changes in the levels of proteins in spinal and supraspinal levels in laboratory animals and suggests a direct correlation between structural changes in the central nervous system and chemotherapy-induced neurotoxicity [128].…”