Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase

Abstract

Many of the widely used anticancer drugs induce dose-limiting peripheral neuropathies that undermine their therapeutic efficacy. Animal models of chemotherapy-induced painful peripheral neuropathy (CIPN) evoked by a variety of drug classes, including taxanes, vinca alkaloids, platinum-complexes, and proteasome-inhibitors, suggest that the common underlying mechanism in the development of these neuropathies is mitotoxicity in primary nerve sensory axons (PNSAs) arising from reduced mitochondrial bioenergetics [eg adenosine triphosphate (ATP) production deficits due to compromised respiratory complex I and II activity]. The causative mechanisms of this mitotoxicity remain poorly defined. However, peroxynitrite, an important pro-nociceptive agent, has been linked to mitotoxicity in several disease states and may also drive the mitotoxicity associated with CIPN. Our findings reveal that the development of mechano-hypersensitivity induced by paclitaxel, oxaliplatin, and bortezomib was prevented by administration of the peroxynitrite decomposition catalyst Mn(III) 5,10,15,20-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTE-2-PyP5+) without interfering with their anti-tumor effects. Peak CIPN was associated with the nitration and inactivation of superoxide dismutase in the mitochondria, but not in the cytosol, as well as a significant decrease in ATP production within the PNSAs; all of these events were attenuated by MnTE-2-PyP5+. Our results provide continued support for the role of mitotoxicity in the development of CIPN across chemotherapeutic drug classes, and identify peroxynitrite as a key mediator in these processes, thereby providing the rationale towards development of “peroxynitrite-targeted” therapeutics for CIPN.

The Contribution of Mitochondria to Sensory Processing and Pain

“…50 Peroxynitrite decomposition catalysts have been shown to reverse established paclitaxel-induced mechanical hypersensitivity 51 and to also prevent the development of mechanical hypersensitivity induced by paclitaxel, oxaliplatin, and bortezomib. 51,52 Recently, an increase in ROS and reactive nitrogen species (RNS) levels was seen in lumbar DRG following chronic oxaliplatin treatment in mice. 53 SS-31, a novel mitochondria-targeted antioxidant, reversed this oxaliplatin-evoked ROS/RNS increase and also attenuated oxaliplatininduced cold and mechanical hypersensitivities.…”

Effect of the SOD mimetic MnL4 on in vitro and in vivo oxaliplatin toxicity: Possible aid in chemotherapy induced neuropathy

“…Decreased MnSOD activity has been described in different CIN, depending on SOD nitration linked to high levels of species with high oxidizing power [13]. Mitochondria are together sources and targets of O 2 À and other reactive oxygen species (ROS).…”

Cooperativity between remote sites of ectopic spiking allows afterdischarge to be initiated and maintained at different locations

“…Second, whereas phase 1 AD eventually fails because of the relatively large surface area-to-volume ratio characteristic of the axonal compartment, phase 2 AD can continue for much longer because of the smaller surface area-to-volume ratio of the somatic compartment. Although active pumping by the Na-K pump was not explicitly modeled here, it is very likely that energy supplies are more limited within the axon than in the soma, especially if/when dysfunction of axonal mitochondria is a contributing pathogenic factor (Flatters and Bennett 2006; Janes et al 2013), which would exacerbate ion concentration changes. It has been shown that spike-evoked Na influx is similar between soma and axon and that Na clearance from the site of influx is largely due to diffusion rather than pumping (Fleidervish et al 2010), although pumping presumably becomes more important at longer timescales, especially in the context of sustained, high-frequency spiking.…”

“…For instance, the rate of pumping through the Na-K ATPase can be significantly modulated on the basis of recent spiking activity (N. Yu et al 2012). As an active process, such pumping depends on energy considerations including mitochondrial function, which can be compromised in certain conditions such as chemotherapy-induced neuropathic pain (Flatters and Bennett 2006; Janes et al 2013). These changes represent slower processes that would interact with alterations in ion channel expression and function (see above).…”