Investigating The Role of Astrocyte Elevated Gene-1 (AEG-1), a Multifunctional Protein, in The Development and Maintenance of Chronic Pain

Author

Bryan D. Mckiver, Virginia Commonwealth UniversityFollow

Author ORCID Identifier

0000-0002-1447-5803

Defense Date

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

M. Imad Damaj

Second Advisor

Devanand Sarkar

Third Advisor

Aron Lichtman

Fourth Advisor

Dana Selley

Fifth Advisor

John Bigbee

Abstract

In a 2018 report from the U.S. Centers for Disease Control and Prevention, it was estimated that one in five adults in the United States (50 million or 20.4%) suffered from chronic pain. Current pharmacotherapies for chronic pain, such as opioids and serotonin-norepinephrine reuptake inhibitors, have diminished efficacy with long term use and produce severe adverse effects that can hamper the quality of life for patients. It has become quite clear that there is a vital need to develop more efficacious, non-opioid, treatments for chronic pain. Neuroinflammation represents a primary underlying cause of several chronic pain conditions, especially those associated with peripheral nerve damage and autoimmune dysfunction. Astrocyte Elevated Gene 1 (AEG-1) is a multifunctional protein that modulates macrophage activity and regulates inflammation through direct interaction with NF-κB, a transcriptional regulator of proinflammatory cytokine (PIC) expression. We investigated the effects of AEG-1 inhibition in chronic pain using both global (AEG-1 KO) and myelocyte-specific knockout (AEG-1^ΔMAC) transgenic mouse strains. We employed AEG-1 deficient mice in rodent models of paclitaxel (PAC)-induced peripheral neuropathy for Aim 1 studies, while the Complete Freund’s Adjuvant (CFA)-induced chronic inflammatory pain model was used for Aim 2. In Aim 3, we performed initial experiments investigating the efficacy of macrophage-targeting nanoparticles loaded with AEG-1 siRNA (PAMAM-AEG-1si) for the treatment of chronic pain. In Aim one, our results showed that global AEG-1 deletion prevented the development and maintenance of CIPN pathologies induced by PAC, as well as oxaliplatin (OHP). PAC treatment was found to increase AEG-1 and PIC expression in the DRGs of wild type (WT) mice and in peritoneal macrophages isolated from C57BL/6J mice. However, in the absence of AEG-1 expression, PAC-induced neuroinflammation was completely halted in the DRGs of AEG-1 KO mice. This preventative phenotype and PIC expression profile was mirrored in AEG-1^ΔMAC mice, which also displayed reduced NF-κB protein levels and F4/80+ macrophages trafficked to the lumbar DRGs following PAC treatment. In Aim 2, we observed that CFA-induced mechanical and thermal hypersensitivity were reduced in both AEG-1 KO and AEG-1^ΔMAC mice. Additionally, CFA administration was found to upregulate the expression of AEG-1 and several PICs in the lumbar dorsal root ganglia (DRG) of WT mice. However, in the absence of AEG-1, PIC expression mirrored vehicle controls. Lastly, AEG-1^ΔMAC mice displayed similar protective phenotype and PIC expression profile as AEG-1 KO mice and also displayed reduced F4/80+ macrophages trafficked to the lumbar DRGs following CFA treatment. In Aim 3, we observed that PAMAM-AEG-1si selectively reduces AEG-1 expression in macrophages and prevents PAC-induced mechanical and cold hypersensitivity in C57BL/6J mice. We also observed that PAMAM-AEG-1si effectively reverses hypersensitivity induced by both PAC and CFA in C57BL/6J mice. Altogether, these results support that AEG-1 expression in myelocytes represents a novel therapeutic target for the treatment and prevention of chronic pain.

Rights

© Bryan D. Mckiver, 2024

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-9-2024