Coronaridine congeners induce anticonvulsant activity in rodents by hippocampal mechanisms involving mainly potentiation of GABAA receptors
European Journal of Pharmacology. 2024-11-01; 982: 176911
DOI: 10.1016/j.ejphar.2024.176911
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Arias HR(1), Kazmierska-Grebowska P(2), Kowalczyk T(2), Shim Y(3), Caban B(2),
Aman C(3), Allain AE(3), De Deurwaerdère P(3), Chagraoui A(4).
Author information:
(1)Department of Pharmacology and Physiology, Oklahoma State University College
of Osteopathic Medicine, Tahlequah, OK, USA.
(2)Department of Neurobiology, Faculty of Biology and Environmental Protection,
University of Lodz, Lodz, Poland.
(3)Centre National de la Recherche Scientifique, Institut des Neurosciences
Intégratives et Cognitives d’Aquitaine, UMR 5287, Bordeaux, France.
(4)Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen,
France; Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and
Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000
Rouen, France; Normandie University, UNIROUEN, Institute for Research and
Innovation in Biomedicine of Normandy (IRIB) Rouen, France. Electronic address:
.
The coronaridine congeners catharanthine and 18-methoxycoronaridine (18-MC)
display sedative, anxiolytic, and antidepressant properties by acting on
mechanisms involving GABAergic and/or monoaminergic transmissions. Here, we
expanded their pharmacological properties by studying their anticonvulsant
activity in male and female mice using the pentylenetetrazole (PTZ)-induced
seizure test. To determine potential neurochemical mechanisms, the effect of
congeners on monoamine content and kainic acid (KA)-induced epileptiform
discharge was studied in the hippocampus. The behavioral results showed that
coronaridine congeners induce acute anticonvulsant activity in a dose-dependent
but sex-independent manner. Repeated treatment with a subthreshold dose
(20 mg/kg) of each congener produced anticonvulsant activity in a
sex-independent manner, but was significantly higher in male mice when compared
to its acute effect. Using a behaviourally relevant regimen, we found that PTZ
increased dopamine metabolites and serotonin tissue content. Coronaridine
congeners, which induced distinct effects on monoamines, blunted the effect of
PTZ instead of potentiating it, suggesting the existence of another mechanism in
their anticonvulsant activity. The electrophysiological results indicated that
both congeners inhibit KA-induced epileptiform discharges in hippocampal slices.
A key aspect of this study is that the activity of both congeners was observed
only in the presence of GABA, supporting the notion that hippocampal GABAAR
potentiation plays an important role. Our study showed that coronaridine
congeners induce acute anticonvulsant activity in a sex-independent manner.
However, a comparatively higher susceptibility was observed in male mice after
repeated treatment. The underlying hippocampal mechanisms mainly involve GABAAR
potentiation, whereas monoamines play a minor role in the anticonvulsive action.
Copyright © 2024 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejphar.2024.176911
PMID: 39179091 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.