Catalpol and Mannitol, Two Components of Rehmannia glutinosa, Exhibit Anticonvulsant Effects Probably via GABAA Receptor Regulation
Mikyung Kim1,†, Srijan Acharya2,†, Chrislean Jun Botanas1, Raly James Custodio1, Hyun Jun Lee1, Leandro Val Sayson1, Arvie Abiero1, Yong Soo Lee3, Jae Hoon Cheong1, Kyeong-man Kim2,* and Hee Jin Kim1,*
1Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795,
2Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwangju 61186,
3Department of Pharmacology, College of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea
E-mail: hjkim@syu.ac.kr (Kim HJ), kmkim@jun.ac.kr (Kim K)
Tel: +82-2-3399-1609 (Kim HJ), +82-62-530-2936 (Kim K)
Fax: +82-2-3399-1619 (Kim HJ), +82-62-530-2949 (Kim K)
The first two authors contributed equally to this work.
Received: August 6, 2019; Revised: September 17, 2019; Accepted: October 2, 2019; Published online: November 18, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Epilepsy is a brain disorder that affects millions of people worldwide and is usually managed using currently available antiepileptic drugs, which result in adverse effects and are ineffective in approximately 20-25% of patients. Thus, there is growing interest in the development of new antiepileptic drugs with fewer side effects. In a previous study, we showed that a Rehmannia glutinosa (RG) water extract has protective effects against electroshock- and pentylenetetrazol (PTZ)-induced seizures, with fewer side effects. In this study, the objective was to identify the RG components that are responsible for its anticonvulsant effects. Initially, a number of RG components (aucubin, acteoside, catalpol, and mannitol) were screened, and the anticonvulsant effects of different doses of catalpol, mannitol, and their combination on electroshock- and chemically (PTZ or strychnine)-induced seizures in mice, were further assessed. Gamma-aminobutyric acid (GABA) receptor binding assay and electroencephalography (EEG) analysis were conducted to identify the potential underlying drug mechanism. Additionally, treated mice were tested using open-field and rotarod tests. Catalpol, mannitol, and their combination increased threshold against electroshock-induced seizures, and decreased the percentage of seizure responses induced by PTZ, a GABA antagonist. GABA receptor binding assay results revealed that catalpol and mannitol are associated with GABA receptor activity, and EEG analysis provided evidence that catalpol and mannitol have anticonvulsant effects against PTZ-induced seizures. In summary, our results indicate that catalpol and mannitol have anticonvulsant properties, and may mediate the protective effects of RG against seizures.
Keywords: Rehmannia glutinosa, Catalpol, Mannitol, Anticonvulsant, Epilepsy, Gamma-aminobutyric acid (GABA)


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