Mechanisms of action of antihyperglycemic mexicanolides isolated from Swietenia humillis: in vivo and in silico approaches

 

Diabetes mellitus is one of the major non-communicable, chronic and incurable illnesses around the world. In Mexico, as in many countries, medicinal plants are used alone or in combination with allopathic drugs to alleviate the symptoms of the disease. Swietenia humilis is one of the medicinal species used in the country for this purpose [1]. Eight limonoids of the mexicanolide type were isolated from the seeds of the plant, and of them, compounds 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1) and methyl-2-hydroxy-3-β-tigloyloxy-1-oxomeliac-8(30)-enate (2) were established as the main bioactive principles of the species [2]. Thus, the present study was undertaken to investigate the antihyperglycemic mechanism of action of mexicanolides 1 and 2. In vivo experiments with hyperglycemic mice (NAD-STZ, 50 – 130 mg/kg) pretreated with diazoxide (a K_ATP channel activator) revealed that 1 exerted a partial blockade of K_ATP channels. However, pretreatment of the animals with ketanserin (a serotonin 2A/C receptor antagonist) resulted in the loss of their antihyperglycemic effect. Glibenclamide (9.47 mg/kg) and metformin (57.75 mg/kg) were used as positive controls. Thus, 1 and 2 behaved as agonists of serotonin 2A/C receptors [3]. In silico studies of limonoids 1-8 predicted an interaction between these compounds and the serotonin 2C receptor constructed by homology modeling; they interacted in the extending binding area of serotonin 2C receptor. The information generated in this investigation contributes to scientific validation and rational use of this medicinal resource in Mexican folk medicine.

Acknowledgements: This work was supported by a grant from CONACyT (219765) and DGAPA (IN217516). We are in debt to Dirección General de Cómputo y de Tecnologías de Información y Comunicación (DGTIC), UNAM, for providing the resources to carry out computational calculations. B. Ovalle acknowledges a fellowship from CONACyT (240053).

Keywords: Swietenia humilis; mexicanolides; antihyperglycemic; serotonin 2C receptor; molecular docking.

References:

[1] Romero-Cerecero O, Reyes-Morales H, Aguilar-Santamaría L, Huerta-Reyes M, Tortoriello-García J. Use of medicinal plants among patients with diabetes mellitus type 2 in Morelos, Mexico. BLACPMA 2009; 8: 380 – 388

[2] Ovalle-Magallanes B, Medina-Campos ON, Pedraza-Chaverri J, Mata R. Hypoglycemic and antihyperglycemic effects of phytopreparations and limonoids from Swietenia Humilis. Phytochemistry 2015; 110: 111 – 119

[3] Hajduch E, Rencurel F, Balendra A, Batty IH, Downes CP, Hundal HS. Serotonin (5- Hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. J Biol Chem 1999; 274: 13563 – 13568