Document Type

Dissertation - Open Access

Award Date

2019

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Shafiqur Rahman

Keywords

Astroglia, Glutamate transporter, Hippocampus, LDN-212320, Mice, Pain

Abstract

Pain is a devastating public health condition affecting nearly 35% of the world population. In the United State, the economic cost related to acute and chronic inflammatory pain treatment is estimated to be $635 billion annually. The currently approved medications for acute or chronic inflammatory pain include nonsteroidal antiinflammatory, opioids, antidepressants and anticonvulsants which are less effective and associated with severe adverse complications. Therefore, there is a need for the development of alternative strategy by targeting novel mechanisms in the central nervous system. Glial glutamate transporter in the hippocampus and ACC is critically involved in acute and chronic inflammatory pain modulation. We have hypothesized that astroglial GLT-1 in the hippocampus and ACC plays a crucial role in the behavioral, cellular and molecular mechanisms associated with acute and chronic inflammatory pain. The primary goal of the present dissertation is to investigate the role of astroglial GLT-1 in the regulation of behavioral, cellular and molecular mechanisms involved in acute and chronic inflammatory pain in the hippocampus and ACC using animal models of acute and chronic inflammatory pain. We have shown that astroglial GLT-1 activator, LDN-212320, attenuates formalininduced acute inflammatory pain behaviors in mice. In addition, LDN-212320 reverses astroglial GLT-1 downregulation in the hippocampus and ACC and reduces ERK phosphorylation associated with formalin-induced cognitive deficits and anxiety-like behaviors in mice. We have demonstrated that LDN-212320 significantly attenuates CFA-induced tactile allodynia and thermal hyperalgesia. Moreover, LDN-212320 reverses CFAinduced downregulation of astroglial GLT-1 and CX43 expression, inhibits activated microglial markers Iba1, CD11b and p38 and decreases inflammatory cytokine Interleukin 1- in the hippocampus and ACC. Moreover, we have found that LDN- 212320 significantly reverses CFA-induced cognitive deficits and anxiety-like behaviors through the upregulation of pCREB and BDNF, PKA and CaMKII in the hippocampus and ACC. Taken together, our results demonstrate a strong evidence that astroglial GLT-1 modulation in the hippocampus and ACC regulates behavioral, cellular, and molecular mechanisms associated with acute and chronic inflammatory pain and associated cognitive deficits and anxiety-like behaviors. Therefore, targeting astroglial GLT-1 in the hippocampus and ACC could be a novel therapeutic strategy for acute and chronic inflammatory pain and associated cognitive impairments and anxiety-like behaviors.

Format

application/pdf

Number of Pages

261

Publisher

South Dakota State University

Rights

In Copyright - Educational Use Permitted
http://rightsstatements.org/vocab/InC-EDU/1.0/

Available for download on Sunday, December 18, 2022

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