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Therapeutic potential of CB1R activation by Qingyangshen glycoside M1 for seizure relief.
- Source :
-
Journal of Ethnopharmacology . Jun2024, Vol. 327, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as "Qingyangshen" (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated. The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C 21 steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets. To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0–10 μM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CB 1 R), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CB 1 R antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CB 1 R for M1 efficacy. At a concentration of 400 μM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 μM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CB 1 R activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist. These results demonstrated that M1 as a potential CB 1 R activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CB 1 R chemical antagonism. [Display omitted] [ABSTRACT FROM AUTHOR]
- Subjects :
- *CHINESE medicine
*COMPUTER-assisted molecular modeling
*MOTOR ability
*PHOSPHORYLATION
*HERBAL medicine
*APOPTOSIS
*TREATMENT effectiveness
*FISHES
*PROTEIN microarrays
*IMMUNODIAGNOSIS
*CELL lines
*SEIZURES (Medicine)
*GLYCOSIDES
*NERVOUS system
*ANIMAL experimentation
*MEDICINAL plants
*WESTERN immunoblotting
*ANIMAL behavior
*MOLECULAR biology
*CELL survival
*ANTICONVULSANTS
*HUMAN locomotion
*CELL surface antigens
*DRUG antagonism
*PHARMACODYNAMICS
*EVALUATION
Subjects
Details
- Language :
- English
- ISSN :
- 03788741
- Volume :
- 327
- Database :
- Academic Search Index
- Journal :
- Journal of Ethnopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 176296934
- Full Text :
- https://doi.org/10.1016/j.jep.2024.117982