Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation

Abstract

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

Licochalcone A Inhibits Prostaglandin E2 by Targeting the MAPK Pathway in LPS Activated Primary Microglia

“…The BV-2 cell line is derived from a single cell clone and is immortalized by introducing two oncogenes after a J2 virus infection, possibly affecting some signaling pathways, even if morphology and function are somehow comparable to primary microglia [ 42 ]. Furthermore, the comparison of two different species—mouse for BV-2 cells and rat used for primary microglia cultures in this study—might affect the results, as we have discussed previously due to species-specific differences in receptors, enzymes, and signaling pathways [ 43 ]. Additionally, it has been shown that primary microglia underly individual epigenetic priming, modulating inflammatory responses, and result in different reactions of naive microglia to the same stimulus [ 44 ], delivering another explanation for the differences observed.…”

“…However, after 12 h, Licochalcone A only showed a significant reduction of TNFα in a concentration of 20 µM, and after 24 h LPS stimulation, the timepoint we used in this study, no significant effects of Licochalcone A on TNFα release were found [ 17 ], contrasting our results. However, again, two different species, and in this case even different types of cells are compared, possibly explaining differences by functional selectivity and species-dependent effects [ 43 ]. Furthermore, both presented studies used 100 times higher doses (1 µg/mL) of LPS for the stimulation of their cell lines and higher total concentrations of Licochalcone A, further hindering a comparison [ 17 , 18 ].…”

“…As a restriction in this study, we found a high COX-2 activity after the addition of AA already, possibly suggesting preactivated microglia. In previous studies, AA administration alone showed only small effects on COX-2 activity measured by released PGE 2 [ 43 , 47 ]. However, the higher COX-2 activity after the addition of AA might be explained by COX-1 activity as well since the COX-2 assay measures COX-1 and COX-2 activity together.…”

Cannabis Pharmacogenomics: A Path to Personalized Medicine

“…Upregulation of GPR55 mRNA expression was also reported in intestinal inflammation [ 173 ]. The overexpression was associated with the development of Crohn’s disease [ 164 , 174 , 175 ]. The upregulation of GPR55 expression may also play a role in obesity [ 176 ].…”

Anti-Inflammatory Effects of GPR55 Agonists and Antagonists in LPS-Treated BV2 Microglial Cells

“…As discussed before, biased agonism might be responsible for the observed differentiated effects in addition to the different cells or species being used [32]. The role of GPR55 in the regulation of inflammation, therefore, remains the focus of current research.…”