Targeting the Overproduction of Peroxynitrite for the Prevention and Reversal of Paclitaxel-Induced Neuropathic Pain

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and "PN-targeted" therapeutics.

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…The FeTSPP 3 -and its mesityl analog FeTMSP 7 -were also reported as specific ONOO -scavengers (241). FeTM-4-PyP 5 + has often been described as a peroxynitrite decomposition catalyst (77,157,187). (Table 1) and similar electrostatics and, in turn, fairly similar k cat (O 2 $ -).…”

“…At higher levels of Fe, the toxicity is most likely due to the Fenton chemistry-driven $ OH production at the metal site of FeP or at ''free'' low-molecular Fe (273). Were the mechanism of action of FePs versus MnPs indeed as different in mammalian systems as shown in E. coli, our present understanding of the favorable effects often exerted by FePs in animal models of disease would need reconsideration (12,47,77,102,256). The E. coli data illustrate the complexity of the biology of redox-compatible metal complexes and call for caution when interpreting the in vivo data.…”

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

“…Importantly, endoneurial blood flow is increased and nerve degeneration is reduced in CIPN rats by increasing the level of vascular endothelial growth factor, which promotes angiogenesis 49,50 . Recent evidence also shows that mechanical allodynia and thermal hyperalgesia in CIPN rats can be alleviated by systemic treatment with agents that reduce reactive oxygen 20 and nitrogen 22 species, both of which are elevated in association with microvascular dysfunction. Clinically, in addition to CIPN it has often been reported that chemotherapy induces Raynaud's phenomenon 4,5,86 , a condition where patients develop poor capillary blood flow in the fingers and toes.…”

“…Recent parallel studies by other groups suggest that microvascular dysfunction and the resulting production of reactive oxygen and nitrogen species may contribute to neuropathic pain (including chronic constriction injury (CCI) of the sciatic nerve 2,3,31 , painful diabetic neuropathy (PDN) 21,24,42,45,48,74 and chemotherapy-induced painful neuropathy (CIPN) 20,22,49,50 . Therefore, it is expected that treatments aimed at enhancing tissue oxygenation by reducing arterial vasospasm and capillary slow-flow/no-reflow will also relieve allodynia in animal models of nerve constriction, PDN and CIPN.…”

Chemotherapy-Induced Peripheral Neuropathy

“…158,201,202 In fact, the generation of nitroxidative stress, induced by ROS and RNS, has been shown to enhance the sensitivity of nociceptive sensory neurons. 203,204 Chemotherapy-induced ROS and RNS are generated by neurons, supporting satellite cells and inflammatory cells.…”