Abstract
Zingiber officinale is one of the most frequently used medicinal herbs in Asia. Using rodent seizure models, it was previously shown that Zingiber officinale hydroethanolic extract exerts antiseizure activity, but the active constituents responsible for this effect have not been determined. In this paper, we demonstrated that Zingiber officinale methanolic extract exerts anticonvulsant activity in the pentylenetetrazole (PTZ)-induced hyperlocomotion assay in larval zebrafish. Next, we isolated 6-gingerol (6-GIN)—a major constituent of Zingiber officinale rhizoma. We observed that 6-GIN exerted potent dose-dependent anticonvulsant activity in the PTZ-induced hyperlocomotion seizure assay in zebrafish, which was confirmed electroencephalographically. To obtain further insight into the molecular mechanisms of 6-GIN antiseizure activity, we assessed the concentration of two neurotransmitters in zebrafish, i.e., inhibitory γ-aminobutyric acid (GABA) and excitatory glutamic acid (GLU), and their ratio after exposure to acute PTZ dose. Here, 6-GIN decreased GLU level and reduced the GLU/GABA ratio in PTZ-treated fish compared with only PTZ-bathed fish. This activity was associated with the decrease in grin2b, but not gabra1a, grin1a, gria1a, gria2a, and gria3b expression in PTZ-treated fish. Molecular docking to the human NR2B-containing N-methyl-D-aspartate (NMDA) receptor suggests that 6-GIN might act as an inhibitor and interact with the amino terminal domain, the glutamate-binding site, as well as within the ion channel of the NR2B-containing NMDA receptor. In summary, our study reveals, for the first time, the anticonvulsant activity of 6-GIN. We suggest that this effect might at least be partially mediated by restoring the balance between GABA and GLU in the epileptic brain; however, more studies are needed to prove our hypothesis.
Highlights
Epilepsy, a chronic neurological disorder that affects approximately 1% of the population worldwide, is characterized by recurrent, atypical brain activity, which is clinically manifested through various symptoms, such as loss of consciousness and unpredictable convulsions [1]
4-day-old zebrafish larvae were incubated for 24 h in different concentrations of Zingiber officinale rhizome methanolic extract
In the case of the selected model, all subunits possess a modular domain architecture, with amino-terminal domains (ATDs), ligand-binding domains (LBDs) that are localized on the extracellular side of the membrane, transmembrane domain (TMD) spanning the membrane and defining the ion channel pore, and an intracellular carboxy-terminal domain (CTD). 6-GIN was docked to ATDs, LBDs, and TMD of the GluN1/GluN2B NMDA receptor
Summary
A chronic neurological disorder that affects approximately 1% of the population worldwide, is characterized by recurrent, atypical brain activity, which is clinically manifested through various symptoms, such as loss of consciousness and unpredictable convulsions [1]. Compounds with antiseizure activity diminish PTZ-induced hyperlocomotion and decrease the number of LFP based epileptiform-discharges [7,14]. Using this model, the antiseizure activity of various plant-derived constituents have been identified, e.g., oliganthin H from Garcinia oligantha [15], palmatine from Berberis sibirica [13], indirubin from Indigofera arrecta [16], or bisabolene sesquiterpenoids from Curcuma longa [17]. We first assessed the effect of the methanolic extract from ginger rhizomes in the PTZ-induced hyperlocomotion assay in larval zebrafish. We performed in silico study to explain the possible inhibitory activity of 6-GIN and propose the binding sites of 6-GIN at the NR2B-containing N-methyl-D-aspartate (NMDA) receptor
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