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Table 5 A summary of the possible mechanisms involved in the development of oxaliplatin-induced neuropathic pain

From: Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development

Targets Mechanisms References
Na+ channel Prolonged open state and slow inactivation of the Na+ channels in acute OIPN [12, 55,56,57]
Induced abnormalities of Na+ currents in chronic OIPN [58]
K+ channel Increasing the expression of the pro-excitatory K+ channels [59]
Decreased expression of two-pore domain K+ channels (TREK-1 and TRAAK) in DRG [60, 61]
CAG repeat polymorphisms in the KCNN3 gene [62]
Ca2+ channel Oxalate as a calcium chelator contributes to the acute form of OIPN [63]
Increased expression of the Cavα2δ – 1 subunit mRNA and protein in cold hypersensitivity [64, 65]
Reduction in P/Q-, T-, and L-type Cav channel currents [66]
Transient receptor potential channels Up-regulation of the mRNA of the TRPV1, TRPA1, and TRPM8 in cultured DRG neurons [67]
OHP-induced cold allodynia in vivo was found to enhance the sensitivity and expression of TRPM8 and TRPA1 [68, 69]
Oxaliplatin and oxalate cause TRPA1 sensitization to ROS [70, 71]
Transporters CTRs (CTR1) and OCTs (OCT2) mediate the uptake of OHP [48, 72]
ATP7A and ATP7B facilitate the cellular efflux of OHP [73]
Nuclear DNA damage Formation of platinum DNA adducts [57, 74].
Oxidative stress-related mitochondrial damage Neuronal mitochondrial dysfunction resulting in nitro-oxidative stress [2, 75]
Bind to mitochondrial DNA and formation of adducts [76]
Oxidative stress could gate TRPA1, produce nociceptive responses and neurogenic inflammation, and cause demyelination and disruption of the cytoskeleton of peripheral nerves [77, 78]
Lead to electron transport chain disruption and cellular energy failure in DRG neurons [79]
Nrf2 may play a critical role in ameliorating OIPN [67, 80]
Activation of the immune system and neuroinflammation Increased levels of CCL2 and CCR2 accompanied by mechanical hypersensitivity [81]
IL-8 signaling pathway is involved in neuroinflammation [82]
Gut microbiota -TLR4 activation on macrophages [83]
Increased circulating CD4 + and CD8 + T-cells [84]
Glia activation Increase of neuro-immune activation resulting in converted neurotransmission [85,86,87,88,89]
Transient activation of microglia and astrocytes in the spinal cord and supraspinal areas
Schwann cells Mitochondrial dysfunction in Schwann cells [90]
Central nervous system structures and neurotransmitters Altered levels of neurotransmitters, such as catecholamines, histamine, serotonin, glutamate, and GABA [91,92,93]
GLT-1 and GLAST and EAAT1 dysfunction [94, 95]
Caspases and MAP-kinases, Protein kinase C, and PI3K/Akt2 pathway Early activation of the MAP-kinase proteins p38 and ERK1/2, which promotes apoptosis-mediated cell death in rat DRG neurons [96]
Up-regulates the gamma isoforms of PKC and increases in the phosphorylation of gamma/epsilon PKC isoforms [97]
PI3K/Akt2 activation [98]
MicroRNA regulation MiR-15b down-regulation of BACE1 contributes to chronic neuropathic pain [99]
Gut microbiota Different microbe-associated molecular patterns (MAMPs) bind to their TLRs [100]
LPS can directly mediate the gating of TRPA1 and increase calcium influx [101, 102]
Chemotherapy decreased numbers of “beneficial” bacteria, such as Lactobacillus and Bifidobacteria, while Lactobacillus acidophilus exerts anti-tumor effects while preventing the incidence of the toxic adverse events [103, 104]
Microbiome-gut–brain and the neuroimmune–endocrine axis involved in the manifestations of OIPN [103]
  1. ATP7A ATPase Copper Transporting Alpha, BACE1 Beta-secretase 1, Cavα2δ – 1 Calcium voltage-gated calcium channel alpha2/delta subunit, CCL2 C-C motif chemokine 2, CCR2 C-C-Motif Receptor 2, CD4 + Cluster of Differentiation 4 receptors, CD8 + Cluster of Differentiation 8 receptors, CTRs Copper transporters, DNA Deoxyribonucleic acid, DRG Dorsal root ganglion, DRG Dorsal root ganglion, ERK1/2 Extracellular regulated kinase 1/2, GABA γ-aminobutyric acid, GLAST EAAT1, glutamate aspartate transporter, GLT-1 Glutamate transporter 1, IL-8 Interleukin-8, KCNN3 Potassium channel SK3, LPS Lipopolysaccharides, MAMPs Microbe-associated molecular patterns, OCTs Organic cation transporters, OIPN Oxaliplatin induced peripheral neuropathy, PI3K/Akt2 Phosphatidylinositol 3 kinase/ protein kinase B, PKC Protein kinase C, ROS Reactive oxygen species, TLR Toll-like receptors, TLR4 Toll-like receptors 4, TRAAK TWIK-related arachidonic acid-stimulated K+ channel, TREK-1 TWIK—Related K+ channel 1, TRPA1 Transient receptor potential A1, TRPM8 Transient receptor potential cation channel subfamily M member 8, TRPV1 Transient receptor potential vanilloid 1