Microglia and astrocytoma cells express alkylindole-sensitive receptors

Abstract

Two cannabinoid (CB) receptors, CB1 and CB2, have been identified at the molecular level. Evidence suggests that other cannabinoid and cannabinboid-like receptors remain to be identified. Using newly developed compounds, our lab has identified receptors sensitive to alkylindoles (AI) which exhibit a distinct pharmacological profile from CB1 and CB2 receptors and are expressed by both microglia and astrocytomas. Radioligand binding data show that WIN-2, and novel analogues, ST-11 and ST-48, compete for [3H]WIN-2 binding in DBT mouse astrocytoma cells and primary microglia in culture, while classic cannabinoid ligands did not. In microglia, ST-11 and ST-48 increase intracellular cAMP levels, suggesting that AI receptors are GPCRs that couple to Gs. As resident immune cells of the CNS, microglia play many roles in maintaining homeostasis in a healthy brain. AI analogues inhibit both basal and ATP-stimulated microglia cell migration. The compounds did not affect cell viability, yet they did inhibit cell proliferation stimulated by macrophage colony stimulating factor (M-CSF). Interestingly, AI analogues did not modulate effector proteins that characterize M1 or M2 phenotypes. AI analogues also inhibited DBT cell migration, though with lower efficacy. In contrast to microglia, AI analogues did reduce cell viability and basal cell proliferation, suggesting that AI-sensitive receptors expressed by cancer cells may be an effective target to reduce tumor growth. In vivo study of ST-11 formulated in liposomes show that tumor volume was reduced while microglia reactivity was increased. Further study of AI analogues is needed to increase understanding of this phenomenon.