TABLE 1.

Overview of key pathways in the peripheral nerves implicated in CIPN.

Pathway	Details
Ion channels and receptors	CIPN appears to be caused by altered expression of ion channels and receptors, which lead to changes in neural activity (e.g., hyperactivity). For example, oxaliplatin causes prolonged opening of sodium channels (Grolleau et al., 2001; Webster et al., 2005); potassium channels are down-regulated in peripheral and dorsal root ganglia (DRG) nerves in CIPN (Descoeur et al., 2011; Thibault et al., 2012; Zhang and Dougherty, 2014); calcium channel expression is increased in the DRG after paclitaxel, and calcium channel antagonists (e.g., gabapentin) reduce CIPN symptoms in rodents (but not humans) (Flatters and Bennett, 2004; Xiao et al., 2007); CIPN has been associated with increases in expression of TRPV1 (heat-activated) in the DRG (Ta et al., 2010; Hara et al., 2013; Quartu et al., 2014), TRPA1 (cold-activated) expression (Nassini et al., 2011; Zhao et al., 2012), and TRPM8 (mild cold-activated)
Innate immune system and inflammation	The innate immune response and inflammation play a role in CIPN. For instance, the toll-like receptor-4 (TLR4), which is activated by bacterial pathogens, is also activated in the spinal cord in response to chemotherapy (Byrd-Leifer et al., 2001). CIPN symptoms can be reduced or prevented by blocking the TLR4 pathway during chemotherapy by way of an antagonist (Li et al., 2014; Li et al., 2015) or a genetic knockout (Park et al., 2014). Macrophages and inflammatory mediators such as CCL2, IL-1β, and TNF-α are all increased in the DRG during the development of CIPN (Woolf et al., 1997; Binshtok et al., 2008; Zhang et al., 2013; Zhang et al., 2016). These pro-inflammatory mediators cause neuronal hyperexcitability (Sorkin et al., 1997; Onda et al., 2002; Özaktay et al., 2002) by suppressing GABA production and glutamate clearance by spinal astrocytes
Mitochondrial dysfunction	Multiple studies have shown that paclitaxel, docetaxel, and oxaliplatin cause swollen and vacuolated mitochondria (Flatters and Bennett, 2006; Zhao et al., 2012; Zheng et al., 2012) with reduced respiration and ATP production (Zheng et al., 2011; Zheng et al., 2012) in peripheral sensory nerves and the DRG of the spinal cord. Second, oxidative stress is another hypothesis for CIPN development, as mitochondria and other cellular components are major sources of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Waseem et al., 2018). Both ROS and RNS affect neuronal excitability (Gamper and Ooi, 2015), and multiple studies have shown that various ROS scavengers reduce CIPN symptoms from paclitaxel (Kim et al., 2010; Fidanboylu et al., 2011, Janes et al., 2013)
Cell signaling pathways including GPCRs and MAPK	Changes in cell structural integrity (e.g., paclitaxel disrupting microtubules) and cell signaling pathways (e.g., G-coupled protein receptors [GPCRs], protein kinase C [PKC] (Chen et al., 2011), mitogen-associated protein kinase [MAPK] (Scuteri Galimberti et al., 2010) can lead to changes in neuronal growth including apoptosis. Some of these are linked to other above-mentioned pathways such as MAPK signaling as resulting from inflammation contributing to paclitaxel induced CIPN (Li et al., 2015)