6-Gingerol, a Major Constituent of Zingiber officinale Rhizoma, Exerts Anticonvulsant Activity in the Pentylenetetrazole-Induced Seizure Model in Larval Zebrafish

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.

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

“…The PTZ-induced model of tonic-clonic seizures in zebrafish is commonly used for initial screening of potential natural 49 − 51 and synthetic anticonvulsant agents. 29 , 52 Larval zebrafish, when incubated in PTZ solution, experience seizures that behaviorally manifested as a hyperactivity.…”

“…Here, we measured distance traveled within 5-min long time bins and total distance within 30 min observation period. 49 Two-way ANOVA with repeated measures indicated the differences between tested groups of larvae [group: F (5,200) = 113.4, p < 0.001; time: F (5,428) = 248.5, p < 0.001; group × time interaction: F (25,1000) = 44.91, p < 0.001] ( Figure S4A ). One-way ANOVA of total distance traveled confirmed this observation [ F (5,200) = 113.4, p < 0.001] ( Figure S4B ).…”

“…The maximal tolerated dose of ( R )-7 [ ( R )-AS-1 ] was chosen as described previously. 49 For the locomotor activity assessment, 6 dpf larvae were incubated for 24 h at 28.5 °C. Next, vehicle or PTZ (final concentration 20 mM) was added to each well.…”

[6]-Gingerol induces Caspase-Dependent Apoptosis in Bladder Cancer cells via MAPK and ROS Signaling

“…Ginger ( Zingiber officinale ) is one of the most frequently used herbs in traditional Asian medicine 7 . It contains pungent phenolic substances such as 6 -GIN, 6 -shogaol, 6 -paradol, and zingerone 10 .…”

“…The ginger rhizomes ( Zingiber officinale ) are among the most frequently used medicinal herbs 7 . The anti-inflammatory, anti-obesity, antiemetic, antioxidant, antibacterial, and anticancer effects of ginger have been studied 8 , 9 .…”