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

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Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent dose-limiting side effect of chemotherapy treatment and will often result in the discontinuation of a treatment regimen for cancer patients. Taxanes, such as paclitaxel (PAC), are a class of chemotherapeutics that fall into this “high prevalence” category of drugs. There are currently no FDA approved prophylactic or treatment regimens designated to ameliorate CIPN. Peripheral inflammation is a common neurotoxic mechanism among many of the chemotherapeutic agents with a high prevalence of CIPN development in patients. PAC is known to activate peripheral macrophages, leading to a cytotoxic inflammatory response that contributes to the development and maintenance of peripheral neuropathy. Astrocyte Elevated Gene 1 (AEG-1) is a multifunctional protein that operates in a wide variety of intracellular signaling pathways. It has been shown to regulate macrophage activation and mediate cellular inflammation through direct interaction with Nuclear Factor kappa B (NFκB), a key transcription factor protein which regulates the expression of multiple proinflammatory cytokines (PIC). Our preliminary studies demonstrate that nociceptive behaviors and increase in PIC in the dorsal root ganglia (DRG) of mice treated with PAC were significantly reduced in AEG-1 global knockout (KO) mice compared to AEG-1 WT mice, without affecting motor activity and coordination of the animals. We also present data that shows PAC administration increases AEG-1 (MTDH) expression in the DRGs of WT male mice and peripheral macrophages collected from C57BL/6J mice. These findings identify a key role of AEG-1 in regulating nociceptive responses and a potential target for ameliorating CIPN. We hypothesize that AEG-1 mediates PAC-induced neuroinflammation, via macrophage activation leading to the development of CIPN. We will test our hypothesis in Aim 1 by analyzing pain behaviors and various aspects of neuropathy in paclitaxel-induced CIPN in AEG-1 KO and WT mice. We will also assess mRNA expression levels of PIC and protein levels of phosphorylated NFκB in the DRGs collected from PAC treated mice to determine how global AEG-1 deletion impacts PAC-induced neuroinflammation in an NFκB-dependent manner. Aim 2 will investigate the role of macrophage cell AEG-1 expression in PAC-induced neuropathy and neuroinflammation by using myeloid cell- specific conditional AEG-1 KO mouse. Completion of these behavioral and molecular studies will identify AEG-1 expression, particularly in macrophages, as a key driver of neuropathy paving the way for novel therapeutic targets for the treatment or prevention of CIPN.