Biomimicry TRPV1 agonist 6SA attenuates corticosterone-induced depression via targeting Glul-Gm57375 signaling in microglia

Introduction Microglia-mediated neuroinflammation hallmarks the pathophysiology of depression. We recently identified 6-shogaol (6Sh) from the ginger root ( Rhizoma Zingiberis Recens ) as a potent anti-neuroinflammatory and antidepressant drug candidate. Objectives This study aimed to resolve the bioavailability and cost-effectiveness of 6Sh for the development of novel anti-neuroinflammatory drugs against depression. Methods A biomimicry 6Sh analog (6SA) with an amide moeity is chemically synthesized by directly coupling vanillylamine with trans -2-octenoic acid and pharmacologically evaluated in a mouse model of corticosterone-induced depression. Single-cell RNA sequencing (scRNA-Seq) was performed to profile the brain spatial transcriptomic responses to 6SA for molecular insights to define the antidepressant mechanisms. Results As results, 6SA outperforms the parent 6Sh in terms of water solubility, oral bioavailability, cytotoxicity, cost-effectiveness and pharmacokinetic profile. Remarkably, 6SA more effectively attenuated neuroinflammation and depressive-like behaviors while demonstrated good safety profile in mice. Mechanistically, the scRNA-Seq results highlighted two important differentially expressed genes (i.e., Glul and lncRNA Gm57375) in the prefrontal cortex microglia. Strikingly, in vivo and in vitro experiments indicated that 6SA regulated Glul and Gm57375 expression in a TRPV1-dependent manner. Conclusion Thus, 6SA may be a promising drug candidate with the capacity to tune neuroinflammation via targeting the TRPV1–Glul–Gm57375 axis in microglia against depression.