Author ORCID Identifier

0000-0002-9525-1106

Defense Date

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Clinical and Translational Sciences

First Advisor

M. Imad Damaj

Second Advisor

John Bigbee

Third Advisor

Pin-Lan Li

Fourth Advisor

Shijun Zhang

Fifth Advisor

Egidio Del Fabbro

Abstract

Paclitaxel and oxaliplatin are commonly used antineoplastic drugs that cause chemotherapy-induce peripheral neuropathy (CIPN) in up to 90% of patients. The sensory symptoms of CIPN include numbness, loss of proprioception, tingling, spontaneous burning, shooting or electric shock-like pain, mechanical and thermal allodynia, and cold hypersensitivity among others. Affected patients struggle with daily activities, have a low quality of life, and might stop cancer treatment. Unfortunately, there are no effective prophylactic or therapeutic treatments for these side effects. Many studies point to the involvement of inflammation as a major contributor of CIPN pathology. We investigated the effects of genetic (NLRP3 KO and ASC KO) and pharmacological (JC124 compound) inhibitions of NLRP3 inflammasome activation in CIPN-associated sensory changes in mice treated with paclitaxel (Aim 1) and oxaliplatin (Aim 2). The findings of Aim 1 show involvement NLRP3 inflammasome activation and the potential of NLRP3 inflammasome inhibition as a pharmaceutical intervention in PIPN. We observed protective effects of NLRP3 inflammasome inhibition from induction of mechanical and cold hypertensives in NLRP3 KO, ASC KO and C57BL/6J treated with 8 mg/kg cumulative dose paclitaxel. Further subjecting of NLRP3 KO mice to a second treatment of paclitaxel (16 mg/kg total) showed sex differences where male had a significantly deceased mechanical threshold. In contrast, both sexes of NLRP3 KO and JC124-co-treated C57BL/6J mice administered 16 mg/kg cumulative dose paclitaxel as one wave displayed a delayed onset of mechanical hypersensitivity. We also were able to observe elevated levels of IL-1β levels in spinal cords of mice treated with 32 mg/kg paclitaxel. In Aim 2, we investigated the role of NLRP3 inflammasome activation in oxaliplatin-induced peripheral neuropathy (OIPN). First, we characterized OIPN in two different strains of mice (C57BL/6J and Balb/cJ) treated with a low (3mg/kg cumulative) and high (30mg/kg cumulative) dose of oxaliplatin. We observed distinct dose-, sex-, strain-, and time-dependent differences. We utilized the low-dose schedule to assess the prophylactic approach to OIPN via inhibition of NLRP3 inflammasome activation measured by mechanical hypersensitivity. We were not able to observe any protection in NLRP3 KO mice, therefore further testing was halted. The results of these two aims suggest that, depending on the class of the chemotherapeutic agent, activation of NLRP3 inflammasome might play a distinct role in chemotherapy-induced peripheral neuropathy.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-7-2022

Available for download on Monday, August 07, 2023

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