Defense Date

4-3-2020

Graduation Date

Spring 5-8-2020

Availability

One-year Embargo

Submission Type

thesis

Degree Name

MS

School

Rangos School of Health Sciences

Committee Chair

John A. Pollock

Committee Member

Kimberly Williams

Committee Member

Bin Yang

Committee Member

Jelena M. Janjic

Keywords

axonal regeneration, peripheral neuropathy, drug delivery, nanomedicine, COX-2 inhibition, macrophages, inflammation, GAP-43, growth cones, F-actin

Abstract

Celecoxib nanoemulsion (CXB-NE) has been developed as a macrophage targeted analgesics by Dr. Janjic and her team at Duquesne University, (Janjic et al, 2018; Liu et al, 2020; Saleem et al, 2019b; Vasudeva et al, 2014). The CXB-NE nanoemulsion carrying a Nonsteroidal Anti-inflammatory (NSAID) inhibitor of COX-2 activity result in a reduction in PGE2 expression in macrophages. Using CXB-NE in rats that have peripheral nerve injury constricting the sciatic nerve relieves hypersensitivity, a pain-like behavior. The treatment also decreases inflammation associated with this chronic constriction injury (Janjic et al, 2018; Saleem et al, 2019b; Stevens et al, 2019). In this project, we evaluated the potential impact of CXB-NE on neuroregeneration. In CCI, the injury and inflammation damages nerves, leading to axon degeneration distal from the site of injury. While peripheral nerves can regenerate axons, if axonal degeneration continues to occur due to inflammation, then axonal regeneration cannot proceed. Ultimately, axonal regeneration can be an important part of nerve recovery, which in humans can aid in rehabilitation after injury. Since CXB-NE is able to decrease inflammation, we are exploring the effect that CXB-NE has on axonal regeneration in the injured sciatic nerve. To analyze this, we are using immunohistochemistry and epi-fluorescent microscopy to assess the presence of macrophages, Growth Associated Protein (GAP-43), and growth cones as detected through F-actin. The results show that GAP-43, which naturally increases expression during nerve regenerations is precociously activated days earlier than normal when CXB-NE is present. Furthermore, CXB-NE treatment appears to enhance the production of axon growth cones, indicating that inhibiting COX2 with the nanoemulsion therapy promotes axon regeneration. These observations will be discussed in the context of other studies on additional infiltrating inflammatory cells and changes in gene expression that are evident during nerve injury and when CXB-NE treatment provides reduced inflammation and pain-relief.

Language

English

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