Investigation of the Possible Allostery of Koumine Extracted From Gelsemium elegans Benth. And Analgesic Mechanism Associated With Neurosteroids

Abstract

Translocator protein 18 kDa (TSPO) is an evolutionarily conserved 5-transmembrane domain protein, and has been considered as an important therapeutic target for the treatment of pain. We have recently reported the in vitro and in vivo pharmacological characterization of koumine as a TSPO positive allosteric modulator (PAM), more precisely ago-PAM. However, the probe dependence in the allostery of koumine is an important question to resolve, and the possible analgesic mechanism of koumine remains to be clarified. Here, we report the in vivo evaluation of the allostery of koumine when orthosteric ligand PK11195 was used and preliminarily explore the possible analgesic mechanism of koumine associated with neurosteroids. We find that koumine is an ago-PAM of the PK11195-mediated analgesic effect at TSPO, and the analgesic mechanism of this TSPO ago-PAM may be associated with neurosteroids as the analgesic effects of koumine in the formalin-induced inflammatory pain model and chronic constriction injury-induced neuropathic pain model can be antagonized by neurosteroid synthesis inhibitor aminoglutethimide. Although our results cannot fully clarify the allosteric modulatory effect of koumine, it further prove the allostery in TSPO and provide a solid foundation for koumine to be used as a new clinical candidate drug to treat pain.

Recent progress in chemistry and bioactivity of monoterpenoid indole alkaloids from the genus gelsemium : a comprehensive review

“…Its treatment displayed efficient analgesic activity against inflammatory and neuropathic pain in a variety of rodent models 37 . Mechanistic studies revealed that koumine could function as a high-affinity ligand that interacted with translocator protein 18kda positive (TSPO) protein in microglia, thereby inducing TSPO allostery 37 , 38 . TSPO allostery triggered the biosynthesis of neurosteroids, such as allopregnanolone in the spinal cords, which mediated the reduction of neuropathic pain 39 .…”

Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke

“…Gelsemium elegans is a traditional Chinese medicine widely used to treat neuralgia, sciatica, rheumatoid arthritis, and acute pain ( 13 , 14 ). Although multiple compounds are involved in the beneficial effect of Gelsemium elegans , alkaloidal constituents are found to play critical pharmaceutical roles in Gelsemium elegans , including anxiolytic, antitumor, antistress, antipsoriatic, and analgesic activities ( 15 , 16 ). In these pharmaceutical roles, anti-inflammatory is a typical character of alkaloidal constituents of Gelsemium elegans .…”

Reference Genes Screening and Gene Expression Patterns Analysis Involved in Gelsenicine Biosynthesis under Different Hormone Treatments in Gelsemium elegans

“…The whole plant is highly poisonous and is a traditional Chinese herb remedy for many symptoms [22]. Its roots are rich in monoterpene indole alkaloids (MIAs), which have demonstrated excellent antiinflammatory, anti-tumor, anti-anxiety, immunomodulatory, and analgesic effects with promising medical applications [23][24][25][26][27][28]. Gelsenicine is an ingredient of MIAs and is the most toxic alkaloid of G. elegans.…”