Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Bioanalysis

Research Advisor

Bob M. Moore II, Ph.D.

Committee

Kenneth M. Anderson, D.D.S. Mustafa M. Dabbous, Ph.D. Franklin Garcia-Godoy, D.D.S., Ph.D. Anastasios Karydis, D.D.S., Ph.D.

Keywords

Cannabinoids, CB2 Selective Inverse Agonist, Chemokines, Cytokines, Periodontal Inflammation, Periodontitis

Abstract

There are approximately 743 million individuals suffering from chronic periodontitis (PD) making it the sixth most prevalent condition worldwide. The affected adult population in the U.S. are nearly 64.7 million and the healthcare costs exceeds $14 billion. Recently, host response to pathogenic infection has been seen critical to the progression of PD and exhibit increase in various inflammatory markers. Marijuana is well known for its recreational usage and is a risk factor for periodontal disease, which is seen as a concern in society for its negative health consequences. However, many medical conditions can benefit from the pharmacological effects of cannabinoids. Plethora of evidence is available for the use of cannabinoids for the anti-inflammatory and immune modulating activity. The targets for therapeutic intervention include the cannabinoid type 1 and 2 receptors (CB1R and CB2R). The CB2 receptor is an attractive target in the endocannabinoid system (ECS), due to widespread expression in peripheral tissue, upregulated expression during inflammation and lacks adverse psychotropic effects associated with CB1 receptor. The expression of cannabinoid receptors are present in periodontal tissues, and play a role in the physiological protection of tissues against excessive inflammation. Our lead compound SMM-189 is a CB2 inverse agonist, which exhibited anti-inflammatory properties in various primary cell lines. We aimed to address the anti-inflammatory properties seen with cannabinoid synthetic compounds SMM-189 (CB2 selective inverse agonist), HU308 (CB2 selective agonist), and the endocannabinoid anandamide (AEA) in periodontal disease. Our primary investigation led us to evaluate the most potent stimuli for the study, from which IL-1β emerged as the most robust inducer of cytokine and chemokine responses. The study was further expanded to include the most prominent biomarkers associated with infection, inflammation and disease. We addressed the hypothesis that effective inhibition of IL-1β-stimulated primary human periodontal ligament fibroblasts (hPDLF’s) will be seen with SMM-189 and HU308 and AEA. The synthetic cannabinoids exhibit excellent profile as an anti-inflammatory agent, while the endocannabinoid AEA exhibits dualistic effects that exerted both anti-inflammatory and pro-inflammatory effects. Our study revealed that the most potent anti-inflammatory effects were seen with SMM-189, an inverse agonist. Suggesting that targeting the endocannabinoid system in chronic periodontitis by an inverse agonist may lead to the development of novel drug for periodontal therapy. The outcome from this study has provided hopes for the development of drugs that will aid in strategies that will improve public oral health.

ORCID

http://orcid.org/0000-0003-1826-9377

DOI

10.21007/etd.cghs.2017.0570

Comments

Two year embargo expires May 2019.

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