The Role of Astrocyte Elevated Gene-1 (AEG-1), a Novel Multifunctional Protein, in Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment for cancer patients. Taxanes, such as Paclitaxel, are a class of chemotherapeutics associated with high prevalence of CIPN development in patients. Taxanes are known to activate peripheral macrophages, generating a neurotoxic inflammatory response that contributes to the development and maintenance of neuropathy. Astrocyte Elevated Gene-1 (AEG-1) is a multifunctional protein that operates in a variety of intracellular signaling pathways. It has been shown to regulate macrophage activation and mediate cellular inflammation through direct interaction with NFκB, a transcriptional regulator of proinflammatory cytokine (PIC) expression. Our goal is to investigate if AEG-1 contributes to the development and maintenance of Paclitaxel-Induced Peripheral Neuropathy (PIPN) and associated neuroinflammation in dorsal root ganglia (DRG). Twelve- to 24-week old AEG-1 global knockout (KO) and wildtype (WT) male and female mice on C57BL/6J background were used in a model of CIPN produced by administration of four 8 mg/kg, i.p. injections of paclitaxel. Mechanical hypersensitivity and cold sensitivity were assessed via Von Frey filaments and acetone test, respectively. mRNA expression was quantified via qRT-PCR. Plasma level concentrations of paclitaxel were assessed via mass spectrometry. AEG-1 KO mice displayed protection from paclitaxel-induced mechanical hypersensitivity and cold sensitivity, unlike their WT counterparts. Paclitaxel increased the expression of AEG-1 and multiple PIC (TNFα, IL1-β, IL-6) in the DRGs of male WT mice. However, these cytokine levels were unchanged in paclitaxel treated AEG-1 KO male mice. Plasma concentration levels of paclitaxel did not differ between AEG-1 KO or WT mice at any time following drug administration. Our data suggest that AEG-1 plays a significant role in the development and maintenance of paclitaxel-induced mechanical and cold hypersensitivity. And that the expression of AEG-1 mediates paclitaxel-induced neuroinflammation in the DRGs. Grant support from 1R01CA221260-01.