ASPO Abstracts
The Role of Astrocyte Elevated Gene-1 (AEG-1), A Novel Multifunctional Protein, In Chemotherapy-Induced Peripheral Neuropathy.
Category: Survivorship & Health Outcomes/Comparative Effectiveness Research
Conference Year: 2023
Abstract Body:
Purpose of the study: Using genetic mouse models we determined the therapeutic potential of targeting Astrocyte Elevated Gene 1 (AEG-1), an endogenous mediator of inflammation, for the treatment of Chemotherapy-Induced Peripheral Neuropathy. Methods: Adult AEG-1 global knockout (KO) and wildtype (WT) male and female mice (C57BL/6J background) were used in a model of CIPN produced by administration of a cumulative dose of 32 mg/kg, i.p. injections of paclitaxel. Mechanical hypersensitivity and cold sensitivity were assessed via Von Frey filaments and acetone test, respectively. Electrophysiological activity of peripheral nerves was assessed via caudal tail nerve conduction assay. mRNA expression in the dorsal root ganglia (DRG) was quantified via qRT-PCR. Plasma level concentrations of paclitaxel were assessed via mass spectrometry. Results: Unlike their WT counterparts, AEG-1 KO mice displayed protection from paclitaxel-induced mechanical hypersensitivity, cold sensitivity, and peripheral nerve disfunction. Paclitaxel increased the expression of AEG-1 and multiple pro-inflammatory cytokines (TNFα, IL1-β, IL-6) in the DRGs of WT mice. However, pro-inflammatory cytokines levels were unchanged in paclitaxel treated AEG-1 KO mice. Plasma concentration levels of paclitaxel did not differ between AEG-1 KO or WT mice. Conclusions: Our data suggest that AEG-1 plays a significant role in the development and maintenance of multiple paclitaxel-induced pathologies associated with CIPN. The prevention of CIPN by AEG-1 genetic deletion seems to be mediated by neuroinflammation reduction in the DRGs. These data lead us to conclude that targeting AEG-1, potentially with the use of targeted nanoparticles-conjugated to AEG-1 siRNA, may be a significant step towards the development of treatment strategies specifically aimed at preventing or reversing CIPN.
Keywords: CIPN, Chemotherapy, Neuropathy, Cancer Pain, Prevention