Hesperidin Interacts With CREB-BDNF Signaling Pathway to Suppress Pentylenetetrazole-Induced Convulsions in Zebrafish.

Pallavi Sharma,Savita Kumari,Jatin Sharma,Damanpreet Singh,Rituraj Purohit

doi:10.3389/fphar.2020.607797

Abstract

Hesperidin (3,5,7-trihydroxyflavanone 7-rhamnoglucoside) is a β-7-rutinoside of hesperetin (4′-methoxy-3′,5,7-trihydroxyflavanone), abundantly found in citrus fruits and known to interact with various cellular pathways to show a variety of pharmacological effects. The present study was envisaged to understand the anticonvulsant effect of hesperidin in a zebrafish model of pentylenetetrazole (PTZ)-induced convulsions, with the support of in silico docking. Healthy zebrafish larvae were preincubated with hesperidin (1, 5, and 10 µM) for 1 h, before PTZ exposure. Hesperidin treatment significantly increased the seizure latency and minimized PTZ-induced hyperactive responses. A significant reduction in c-fos expression further supported the suppression of neuronal excitation following hesperidin incubation in the larvae exposed to PTZ. The treatment also modulated larval bdnf expression and reduced the expression of il-10. The results of in vivo studies were further supported by in silico docking analysis, which showed the affinity of hesperidin for the N-methyl-d-aspartate receptor, the gamma-aminobutyric acid receptor, Interleukin 10 and the TrkB receptor of brain-derived neurotrophic factor. The results concluded that hesperidin suppresses PTZ-mediated seizure in zebrafish larvae through interaction with the central CREB–BDNF pathway.

Highlights

Epilepsy is a chronic brain disorder affecting the lives of around 70 million people worldwide, and around 23 million people in Asia alone (Trinka et al, 2019)
Hesperidin molecule formed hydrogen bonds with the residues Glu106, Gln110, and Glu236, whereas hydrophobic interactions with residues Glu106, Gln110, Tyr175, Phe176, Ser208, and Thr233 obtained with NMDAR receptor
Based on the hydrogen dehydration (HYDE) scoring function’s scores, we found that the hesperidin molecule showed varied levels of interaction with the studied receptors

Summary

INTRODUCTION

Epilepsy is a chronic brain disorder affecting the lives of around 70 million people worldwide, and around 23 million people in Asia alone (Trinka et al, 2019). Huang et al (2012) studied the neuroprotective effect of hesperetin and hesperidin against A-β1-42 induced autophagy and impairment of glucose utilization in Neuro-2A cells. In another study intraperitoneal administration of hesperidin in rats attenuated the kainic acid-induced extracellular glutamate release and neuronal loss in the hippocampal CA3 area, suggesting that hesperidin can cross the blood-brain barrier per se (Chang et al, 2015). Zebrafish (Danio rerio) model of PTZ-induced seizures and hyperactive response analysis was used to study the effect of hesperidin. The findings of in silico and in vivo studies were further corroborated with the gene expression analysis to understand the antiseizure mechanism of hesperidin

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION

CONCLUSION

ETHICS STATEMENT