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

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.

Dendrobium catenatum Lindl. Water Extracts Attenuate Atherosclerosis

“…Zebrafish are a unique vertebrate model that has characteristics of invertebrate models (small size, powerful genetic tractability, high fecundity, ease of maintenance, and relatively low cost) and the advantage of evolutionary conservation in mammals. Thus, zebrafish are invaluable for studying vertebrate development and physiology as well as for modelling human diseases, such as convulsion, epilepsy, and nonalcoholic fatty liver disease [ 28 – 30 ].…”

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

“…The NMDAR-CREB-BDNF pathway plays an important role in inhibiting epileptic seizures (Yu et al, 2019;Sharma et al, 2021). Recent studies have indicated that CREB is involved in the etiology of epilepsy (Wang G. et al, 2020).…”

The Role of Brain-Derived Neurotrophic Factor in Epileptogenesis: an Update

“…In addition, it has been found that CREB is an important nuclear transcription factor that regulates signaling pathways in the brain and is closely related to the expression of its downstream BDNF proteins, forming the CREB/BDNF pathway (Jiang et al, 2021). A recent study showed that hesperidin can promote the activation of the CREB-BDNF pathway and maintain physiological levels of BDNF to inhibit pentylenetetrazol-induced convulsions in zebrafish (Sharma et al, 2020). Thus, these drug studies suggested that BDNF expression may inhibit epileptogenesis from a side as well.…”

“…BDNF is an important member of the neurotrophic factor family. It has a major role in promoting neuronal survival, growth and differentiation during the development of the CNS (Binder, 2004;Sharma et al, 2020); moreover, it can maintain the survival and function of the nervous system and promotes neuro-regeneration after injury (Song et al, 2008;Sun and Alkon, 2019). It was found that BDNF mainly exerts its effects through binding to at least two membrane receptors: tyrosine kinase receptor B (TrkB) and low affinity neurotrophic factor receptor (LNGFR, also known as p75) (Carito et al, 2014).…”