Cyclooxygenase-2 (COX-2) is a prostaglandin-generating enzyme that exhibits low basal expression levels and is upregulated in the central nervous system (CNS) in response to inflammatory stimuli. COX-2 has been implicated in the microglial-mediated neuroinflammatory and neurodegenerative processes of multiple sclerosis (MS), a demyelinating autoimmune disease. To study COX-2 activity and the role it may play in demyelination, a novel PET radiotracer specific for COX-2, [11C]BRD1158, was developed and evaluated in the lysolecithin rodent model of focal demyelination with PET-MR imaging. Preliminary results of this pilot pre-clinical study confirmed our hypothesis that the properties of [11C]BRD1158 enable visualization and monitoring of COX-2 activity under pathological conditions induced by LPC. Radiotracer uptake correlated positively with disease progression at the site of LPC injection in male rats, peaking at day 7 and resolving by day 28. Treatment with an FDA-approved MS therapy, Siponimod, diminished the increase in COX-2 activity and tracer uptake at the lesion site and throughout the brain in both male and female rats. The results from the present study will inform future pre-clinical and translational work that validates the use of [11C]BRD1158 to image COX-2 activity as a marker of underlying inflammation in MS, leading to a better understanding of pathological and inflammatory processes in MS development and progression.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44005 |
| Date | 10 March 2022 |
| Creators | Wang, Jessica |
| Contributors | Thomas, Kevin C. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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