Defense Date

2-23-2023

Graduation Date

Spring 5-5-2023

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Biological Sciences

Committee Chair

John Pollock

Committee Member

Jelena Janjic

Committee Member

Jan Janecka

Committee Member

Lauren O'Donnell

Committee Member

Jill Dembowski

Keywords

sex differences, neuroinflammation, nanotherapeutic, celecoxib, COX-2, chronic constriction injury, CCI, RNA-seq, neuroimmune response, nanotheranostic

Abstract

Until recently, the majority of preclinical neuroinflammatory studies were performed on males. Because of this, less is known about the female neuroinflammatory response to injury, formation of pain, or response to pain-relieving therapies. The neuroinflammatory response is multifaceted with neuronal, glial, and immune cells all contributing to the induction and resolution of neuroinflammation. During this response, macrophages typically undergo an upregulation of cyclooxygenase-2 (COX-2) leading to the production of prostaglandin E2 (PGE2), which is linked to neuronal sensitization and pain. Non-steroidal anti-inflammatory drugs (NSAIDs) attenuate PGE2 by the inhibition of COX-2. A limitation with NSAIDs is that due to the systemic dosage needed to achieve neuropathic pain relief there are risks of off-target toxicity. In collaboration with the Janjic Lab, a novel COX-2 inhibiting theranostic nanoemulsion has been seen to alleviate mechanical hypersensitivity in male rats who have undergone chronic constriction injury (CCI); however, how it works to alleviate female neuropathic pain remained unknown. This study evaluated the efficacy of 1X CXB-NE (0.24 mg/kg) in relieving neuropathic hypersensitivity and saw that females experienced less relief. Increasing the concentration to 10X CXB-NE (2.4 mg/kg) resolved this sex difference with equivalent relief being observed. Knowing the therapeutic works differently in females than in males, we furthered our understanding by transcriptionally evaluating the sex differences during neuroinflammation and relief. Here we found that how males and females responded to treatment was unique. Following neuroinflammatory induction, both sexes had an upregulation of a CREB binding protein, activating transcription factor 3 (ATF-3); following 10X CXB-NE treatment, which only females had a significant down regulation of this gene. Interestingly, it has been seen that ATF-3 is a transcriptional regulator to the COX-2 expression. Males on the other hand appear to have an upregulation of neutrophil involvement, specifically with S1008A and S1009A, which are markers for the release of neutrophil extracellular traps. This body of work shows for the first time that female neuropathic pain can be relieved using a COX-2 inhibiting theranostic nanoemulsion treatment, and that how COX-2 inhibition provides relief is different in males and females.

Language

English

Additional Citations

B. Deal, L. Reynolds, C. Patterson, J. M. Janjic, J. A. Pollock. (2022). Behavioral and inflammatory sex differences revealed by celecoxib nanotherapeutic treatment of peripheral neuroinflammation. Scientific Reports. 12, 8472. https://doi.org/10.1038/s41598-022-12248-8.

M. Saleem, A. Stevens, B. Deal, L. Liu, J. M. Janjic, J. A. Pollock (2019). A new best practice for validating tail vein injections in rat with near infrared labeled agents. JoVE - J. Vis. Exp., (146), e59295, doi:10.3791/59295.

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