8-aminoguanine for prevention and treatment of chemotherapy-induced peripheral neuropathy

Current treatment protocols for most types of cancers require chemotherapeutic agents which are associated with significant side effects, including chemotherapy-induced peripheral neuropathy (CIPN). CIPN manifests as numbness and tingling in the glabrous skin of the hands and feet which often progresses to pain and hypersensitivity to mechanical and cold stimuli. We tested the hypothesis that CIPN is due, at least in part to an increase in purine nucleoside phosphorylase (PNPase) activity, resulting in a shift from anti- to pro-inflammatory purine metabolites. A key prediction of this hypothesis is that inhibition of PNPase can prevent or reverse CIPN. We confirmed a robust mechanical hypersensitivity and loss of intra-epidermal nerve fiber (IENF) density in the glabrous skin following administration of paclitaxel (PAC). The endogenous inhibitor of PNPase, 8-aminoguanine (8-AG), given prior to PAC or 72 hours following the last dose of PAC blocked mechanical hypersensitivity and loss of IENF. Importantly, 8-AG given 72 hours after PAC: 1) reduced levels of pro-inflammatory purines and a biomarker for oxidative stress, 2) increased expression of Growth Associated Protein-43 (GAP-43), 3) increased expression of Mst3b (facilitates axonal regeneration), 4) decreased expression of the membrane protein neurite outgrowth inhibitor-A (Nogo-A), and 5) increased expression of NMNAT2 (an NAD+ producing enzyme). We replicated the effect of 8-AG on PAC-induced mechanical hypersensitivity with shRNA-induced knockdown of PNPase. These findings are consistent with the hypothesis that CIPN is due in part to increased PNPase activity such that PNPase inhibition reduces oxidative injury and cellular damage associated with PAC treatment.