8-Aminoguanine protects against paclitaxel-induced neural degeneration and mechanical allodynia
Lori A. Birder, Amanda Wolf-Johnston, Jonathan Franks, Mara L.G. Sullivan, Simon C. Watkins, Anthony J. Kanai, Vladimir B. Ritov, Edwin K. Jackson
Lori A. Birder, Amanda Wolf-Johnston, Jonathan Franks, Mara L.G. Sullivan, Simon C. Watkins, Anthony J. Kanai, Vladimir B. Ritov, Edwin K. Jackson
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Research Article Cell biology Neuroscience Oncology

8-Aminoguanine protects against paclitaxel-induced neural degeneration and mechanical allodynia

Abstract

Current treatment protocols for most types of cancers require chemotherapeutic agents that are associated with significant side effects, including chemotherapy-induced peripheral neuropathy (CIPN). Currently, there are no effective CIPN prevention strategies, and current treatment approaches remain limited. The enzyme purine nucleoside phosphorylase (PNPase) actively modulates both oxidative injury and cellular damage. Here, we tested the hypothesis that the signs and symptoms of CIPN are due to a chemotherapy-induced dysregulation of the purine metabolome. We assessed the effect of PNPase inhibition on paclitaxel-induced (PAC-induced) CIPN. Female adult Sprague-Dawley rats were treated with PAC and randomized to oral treatment with either the PNPase inhibitor 8-aminoguanine (8-AG) or its vehicle. Some rats were injected with shRNA against PNPase prior to PAC injections. PAC-treated rats exhibited multiple abnormalities: mechanical allodynia and changes in damaging purines, intraepidermal nerve fiber (IENF) density, and signaling cascades involved in mitochondrial disruption and axonal damage. Inhibition of PNPase improved behavioral function (mechanical allodynia), rescued the loss/damage of IENF, and normalized markers for mitochondrial dysfunction and nerve damage. These findings support the hypothesis that inhibition of PNPase prevented (and potentially reversed) CIPN through several mechanisms that included a reduction in neuronal damage and development of mechanical allodynia.

Authors

Lori A. Birder, Amanda Wolf-Johnston, Jonathan Franks, Mara L.G. Sullivan, Simon C. Watkins, Anthony J. Kanai, Vladimir B. Ritov, Edwin K. Jackson

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Figure 2

8-Aminoguanine attenuates PAC-related changes in mechanical sensitivity.

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8-Aminoguanine attenuates PAC-related changes in mechanical sensitivity....
PAC increased sciatic nerve responses to tactile mechanical stimuli, and this was prevented by 8-Aminoguanine (8-AG) (A, n = 6–21 per group) or restored to responses similar to that of untreated control rats by 8-AG given 72 hours following PAC treatment (B, n= 8-14 per group). 8-AG’s effect on mechanosensitivity was restricted to PAC-treated animals. We found a similar response in sciatic nerve responses to tactile mechanical sensitivity between vehicle controls and rats treated with 8-AG without PAC (C, n = 6 to 14). The 8-AG effect was restricted to PAC-treated rats; control rats were not affected by 8-AG. Two-way ANOVA (main effects and interactions, P < 0.0001) followed by Fisher’s least significant difference test show that PAC/8-AG group was significantly different from the other 3 groups but that the other 3 groups are not different from each other. PNPase knockdown attenuates PAC-related changes in nerve functions. PAC increased sciatic nerve responses to tactile stimuli relative to controls. This mechanical hypersensitivity was prevented (D, n = 4 per group) by injection of a lentiviral-based shRNA to knockdown the expression of PNPase in the sciatic nerve. Injections of sham viral particles (i.e., the shRNA cassette contained a scrambled sequence) had no effect on PAC changes in nerve functions. Representative immunoblots are shown; data are calculated as relative intensity normalized to total protein loading control (LC). All samples were run on the same blot, but representative samples were not contiguous. Data are presented as mean ± SD. Ordinary 1-way (A, P < 0.0001; B, P < 0.0001; C, P < 0.0001) ANOVA (followed by a Fisher’s least significant difference test between groups, *P < 0.05, ** P < 0.01, ***P < 0.001 ****P < 0.0001.