Date of Graduation

Summer 2022

Degree

Master of Science in Biology

Department

Biology

Committee Chair

Paul Durham

Abstract

Migraine and temporomandibular disorders (TMD) are prevalent, debilitating orofacial pain conditions involving peripheral and central sensitization of the trigeminal system. The pro-inflammatory neuropeptide calcitonin gene-related peptide (CGRP), which is synthesized and secreted from trigeminal ganglion neurons, is implicated in the underlying pathology of migraine and TMD. Secreted CGRP modulates the excitability state of neurons and glial cells that express CGRP receptors. Recent studies from our lab in preclinical models of migraine and TMD have provided evidence that dietary supplementation with a proanthocyanin-enriched grape seed extract (GSE) inhibits trigeminal pain signaling. The effect of GSE was blocked by an antagonist of the GABAB receptor, which is expressed on primary trigeminal neurons. My study aimed to investigate the cellular mechanisms by which GSE functions to modulate CGRP expression using primary trigeminal ganglion cultures. The effect of GSE on CGRP secretion from trigeminal neurons was determined by radioimmunoassay. To determine if the effects of GSE involve modulation of CGRP expression or the GABAergic system, changes in the expression of CGRP, GAD 65/67, GABAA receptor, and GABAB1 and GABAB2 receptor subunits were investigated by immunocytochemistry. GSE significantly inhibited the basal level of CGRP secretion but did not alter the neuronal expression of CGRP. GAD 65/67 expression levels in neurons were increased in response to GSE incubation. No change in the neuronal expression of GABAA was observed in response to GSE. GABAB1 expression in neurons, satellite glial cells, and Schwann cells increased in response to GSE. GABAB2 expression was elevated in satellite glia and Schwann cells. My findings support the notion that GSE inhibition of basal CGRP secretion involves increased neuronal GAD 65/67 and GABAB receptor expression. GSE repression of CGRP release in the ganglion coupled with increased GABAB1 and GABAB2 glial cell expression would suppress neuronal excitability and the development of peripheral sensitization. In summary, I propose that GSE mediates neuroprotective effects that support its potential as a nutraceutical therapeutic in the management of migraine and TMD.

Keywords

neuroprotective, trigeminal ganglion, peripheral sensitization, calcitonin gene-related peptide, grape seed extract, gamma-aminobutyric acid

Subject Categories

Biology | Molecular and Cellular Neuroscience

Copyright

© Sophia Rose Antonopoulos

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