EFFECTS OF CANNABINOID 2 RECEPTOR ACTIVATION IN BRAIN MICROVASCULAR ENDOTHELIAL CELLS
| Autor: | Bullock, Trent Allen |
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| Jazyk: | angličtina |
| Rok vydání: | 2024 |
| Předmět: | |
| Druh dokumentu: | Text |
| DOI: | 10.34944/dspace/10250 |
| Popis: | Across almost all types of neurological pathophysiology, inflammation and corresponding breakdown of the Blood Brain Barrier (BBB) are hallmarks of injury/disease progression. In fact, BBB disruption can occur early during neuropathophysiological development, in many cases even before neurological and cognitive impairments become apparent. Whether as an early causative factor, a side effect, or both as it pertains to neurological injury/disease, BBB breakdown and dysfunction represents a novel and under investigated target for therapeutic development, especially for neurological pathologies with unmet therapeutic needs. Toward this goal, the endocannabinoid system (ECS) has emerged as a promising biological target for drug discovery efforts. Particularly, the Cannabinoid 2 Receptor (CB2R) has been proposed as a druggable target due to its anti-inflammatory effects and since it is not associated with the neurological side effect profile representative of Cannabinoid 1 Receptor (CB1R) drugs. Interestingly, neuroinflammatory conditions promote upregulation of CB2R on brain microvascular endothelial cells (BMVECs) suggesting a possible role toward resolution of inflammation in this cell type. Moreover, previous research has shown promising effects of CB2R agonists on cerebrovascular function, although these effects cannot be directly attributed to endothelial CB2R. The central hypothesis of this research is that endothelial CB2R activation confers effects which are vascular protective and that promote BBB repair, (irrespective of the effects of CB2R in other central nervous system (CNS) cell types). To address this hypothesis, endothelial CB2R expression dynamics were assessed following experimental Traumatic Brain Injury (TBI) followed by a series of assays to assess the therapeutic potential of a novel chromenopyrazole based CB2R agonist, PM289. Results of these experiments demonstrated upregulation of CNR2, the gene which encodes CB2R, following in vivo experimental TBI and in vitro cytokine induced inflammation. Moreover, PM289 exhibited robust CB2R-dependent therapeutic potential by partially restoring TNFa-induced physical barrier disruption, attenuating TNFa-induced ICAM1 upregulation, and promoting rapid monolayer repair following electrolytic wound. Mechanistically, these effects may be explained via CB2R-dependent inhibition of NFkB/P65 signaling. Overall, these results are supportive of the notion that CB2R in BMVECs could aid in vascular protection and promote BBB function in the context of neuroinflammation. Future studies are warranted to understand the in vivo therapeutic efficacy of PM289 in a variety of injury/disease models. Additionally, alternative cell signaling mechanisms should be considered including a comprehensive examination of potential interplay between ECS components and candidates that fall under the umbrella of the endocannabionoidome (ECBome). Biomedical Sciences Ph.D. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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