Figure 4.

The actions of anticancer drugs (left column) and flavonoids (right column) on a dorsal root ganglion. (a) Simplified Overview. Flavonoids counteract anticancer drugs and increase mitochondrial damage, proinflammatory cytokine production, receptor sensitization, and the likelihood of an action potential. Also depicted is how anticancer drugs increase satellite glial cell coupling and excitability. (b) Anticancer Drugs on Proinflammatory Cytokine Production at the DRG. Anticancer drugs increase the translation of proinflammatory cytokines, prostaglandins, and NO through SIRT1 pathway downregulation and NF-κB activation. This leads to receptor sensitization and an increased likelihood of an action potential firing; (c) Flavonoids on Anticancer Drug- Induced Proinflammatory Cytokine Production in the DRG. Flavonoids counteract anticancer drugs’ actions at the DRG by inhibiting the translocation of NF-κB, upregulating the SIRT1 pathway, and inhibiting the production of proinflammatory cytokines and prostaglandins. These actions decrease inflammation and consequently decrease the likelihood of AP firing and receptor sensitization; (d) Anticancer Drugs on Ion Channels and NT Production at the DRG. Anticancer drugs increase the expression of ion channels such as TRPV1 and N-type VGCC, increasing intracellular Ca²⁺ concentrations and consequently increasing NT release. It also results in a dorsal root reflex; (e) Flavonoids on Anticancer Drug-Induced Increases in NT Production and Ion Channel Expression. 6-MeOF triggers GABAA receptors, decreasing an AP’s likelihood and consequently reducing NT release and alleviating pain; (f) Anticancer Drugs on the DRG’s Oxidative Stress Level. Anticancer drugs increase mitochondrial oxidant production, resulting in lipid peroxidation and tyrosine nitrosylation, lowering GSH levels in the cell and increases oxidative stress, causing neuronal damage; (g) Flavonoids on Anticancer Drug-Induced Increases in DRG Oxidative Stress. Flavonoids counteract the increase in oxidative stress by increasing the translation of GSH and directly scavenging reactive oxygen species; (h) Anticancer Drugs on Satellite Glial Cells. Anticancer drugs increase the expression of gap junctions that connect astrocytes surrounding the same and different DRGs. They also connect SGCs and neurons. Ca²⁺ waves travel through these gap junctions, reducing the membrane potential of SGCs and increasing the likelihood of AP firing in neurons. The Ca²⁺ waves are hypothetically generated by the anticancer drug-induced increase in P2X levels following inflammation. Oxaliplatin blocks the production of Kir4.1, disrupting the extracellular concentration of K⁺ and leading to an increased likelihood of an AP; (i) Flavonoids on Anticancer Drug Effects in Satellite Glial Cells. No relevant research was found on how flavonoids counteract anticancer drug effects on SGCs.