Researchers at the Department of Physiology in the School of Medicine at Trinity College Dublin (TCD) are undertaking new projects to develop cannabis-based therapeutics that target key cellular mechanisms underlying Multiple Sclerosis (MS) pathogenesis.
Dr. Eric Downer leads the Translation Neuroimmunology Research laboratory at the Trinity Biomedical Sciences Institute (TBSI), conducting research in MS and related neuroinflammatory disorders. In projects funded by the Irish Research Council and the Provosts PhD Project Awards at TCD, the laboratory is investigating cellular targets with relevance to the pathogenesis of MS. The targets are toll-like receptors (TLRs), a family of receptors expressed on immune cells in the human body that act to detect and combat infection by microbes, most notably viruses and bacteria. These receptors control intricate inflammatory signalling responses within cells and tissues. For quite some time, a body of peer-reviewed published research has identified that these receptors are associated with the pathogenesis of MS. Indeed, data published from Dr. Downer’s laboratory has shown that in immune cells isolated from people with MS, compared with immune cells from non-MS subjects, the TLR receptor signalling mechanisms are “switched on” in terms of their inflammatory status [1].
Following this discovery, the laboratory asked the following question: If inflammation controlled by TLRs on immune cells is heightened in MS, can novel therapeutics in the form of cannabinoids target these receptors to act as anti-inflammatories? Cannabinoids include the “plant-derived” molecules found in the plant Cannabis sativa L. (C. sativa), alongside a fascinating second cannabinoid group that incorporates the endogenous cannabinoids, commonly known as endocannabinoids. As discussed in a previous ezine issue, basic research continues to elucidate how the cannabinoid system is intricately linked to the function of the immune and nervous systems, and exciting data suggest therapeutic potential of the cannabinoid system in the human body.
In one of the latest research projects funded by the Provosts PhD Project Awards at TCD, Melody Cui Sun, a PhD student in the laboratory, is assessing viral signalling via the TLRs on endosomal compartments within immune cells. Endosomes are vesicles located within cells that act to sort intracellular cargo such as proteins among separate cellular compartments. These organelles also contain TLRs which recognize and respond to components of microbes (nucleic acids). Once microbes are recognized, these receptors trigger cellular responses to combat the infection. Importantly, if this system of defense becomes offset or dysregulated, it can promote inflammatory or autoimmune responses. Melody is assessing the impact of plant-derived cannabinoids on such signalling networks.
Dr. Downer’s team was also recently awarded an Irish Research Council Enterprise Partnership Scheme grant in partnership with Dr. Jack Prenderville, Director, Transpharmation Limited. This research will build on the expertise of Dr. Downer's team and Transpharmation's expanding inflammation service portfolio. Under this award, PhD candidate Almudena Otálora Alcaraz, is establishing assays to investigate novel therapeutics in human immune cells, initially focusing on the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome. The NLRP3 inflammasome has a well-established function in innate immunity. Importantly, the NLRP3 inflammasome is closely associated with the pathogenesis of neuroinflammatory conditions, and evidence suggests that the inflammasome may be a therapeutic target in disorders such as MS. This project is establishing inflammasome assays in cells associated with MS pathogenesis, and this suite of in vitro assays will provide a platform for assessing novel compounds (including cannabinoids) for anti-inflammatory efficacy. The overarching goal of this project is to define the role of the inflammasome in MS and to identify novel inflammasome inhibitors that have efficacy in cells from people with MS.
Dr. Downer said:
“It is hoped that these MS projects will provide evidence that various components of the hemp plant possess anti-inflammatory properties. We hope that this will broaden the therapeutic consideration of components of the cannabis plant, in addition to currently available cannabinoid-based medicines, in MS.”
L-R: Dr. Jack Prenderville (Transpharmation Limited), Dr. Eric Downer (PI), Almudena Otálora Alcaraz (PhD), Melody Cui Sun (PhD)
Photo by: Aidan Kelly
1. Crowley, T., et al., Front Cell Neurosci, 2015. 9: p. 284.