Abstract
Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E2. However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases.
Highlights
Oxidative stress has recently gained more attention in the etiology and pathogenesis of neurological and psychiatric diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and depression [1,2]
Available G-protein coupled receptor 55 (GPR55) agonists, such as O-1602, and GPR55-antagonists like ML-193 are commonly used in GPR55 research, to evaluate GPR55-specific molecular pathways and effects
Besides 8-Iso-PGF2α-levels, we examined the antioxidative capacity with the oxygen radical antioxidant capacity (ORAC) activity assay, which compares antioxidative properties of compounds to a vitamin E analogue named trolox
Summary
Oxidative stress has recently gained more attention in the etiology and pathogenesis of neurological and psychiatric diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and depression [1,2]. Treatment of neurological and psychiatric diseases still focuses on symptomatic relief without targeting the underlying causal pathological molecular mechanisms. Evaluating the role of different receptors and pathways in the homeostasis of oxidative stress in the central nervous system (CNS) might offer new opportunities in the therapy of neurological and psychiatric diseases. Besides LPI, several commercially available as well as endogenous ligands show agonistic or antagonistic activity at the GPR55 [7,9]. Available GPR55 agonists, such as O-1602, and GPR55-antagonists like ML-193 are commonly used in GPR55 research, to evaluate GPR55-specific molecular pathways and effects
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