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Acteoside Isolated from Colebrookea oppositifolia Smith Attenuates Epilepsy in Mice Via Modulation of Gamma-Aminobutyric Acid Pathways

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Abstract

The present study was aimed to evaluate the anticonvulsant activity of acteoside and explore its mechanism of action. Initially, the acteoside was evaluated in maximal electroshock (MES) and pentylenetetrazole (PTZ)–induced convulsions, and later it was evaluated against N-methyl-d-aspartic acid (NMDA)–induced mortality in Swiss albino mice. Based on the response in these models, further evaluations were performed to explore the mechanism of action. In the results, the acteoside (10, 25, and 50 mg/kg) has shown significant anticonvulsant activity in the PTZ model (p < 0.01 for all doses); however, there was no protection observed in MES and NMDA models. Therefore, further mechanism-based studies were performed on the PTZ model, and the outcomes have revealed that there was a significant reduction in GABA (p < 0.01 for both regions) and elevation of glutamate (p < 0.01 for both regions) in the cortex and hippocampus regions of PTZ-treated animals. Further, the antioxidant levels (SOD, catalase, GPx, GR, GSH, LPO) were altered significantly (p < 0.01 for all parameters), with reduced GABAA mRNA levels (p < 0.01) in the PTZ control compared with the normal control. Interestingly, co-administration of acteoside (25 mg/kg) (p < 0.01 for all parameters) has restored all the PTZ-induced alterations compared to PTZ-control. Moreover, the anti-PTZ action of acteoside was completely blocked in the presence of flumazenil, and thus confirmed the GABAergic mechanism behind the anticonvulsant activity of acteoside. Besides, actophotometer and rotarod tests have confirmed that the acteoside is free from central side effects like motor incoordination and locomotor deficits.

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Abbreviations

ANOVA:

Analysis of variance

CMC:

Carboxymethyl cellulose

CPCSEA:

Committee for the Purpose of Control and Supervision of Experiments on Animals

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

ED:

Effective dose

EDTA:

Ethylenediaminetetraacetic acid

FT-IR:

Fourier transform-infrared spectroscopy

GABA:

Gamma-aminobutyric acid

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Reduced glutathione

HLTE:

Hind limb tonic extensor

HLTF:

Hind limb tonic flexion

HPLC:

High-performance liquid chromatography

LC-MS/MS:

Liquid chromatography–mass spectroscopy

LD:

Lethal dose

LPO:

Lipid peroxidation

mA:

Milliamps

MCO:

Methanolic root extracts of C. oppositifolia

MDA:

Malondialdehyde

MES:

Maximal electroshock

MPA:

3-Mercaptopropionic acid

NMDA:

N-methyl-d-aspartic acid

OPA:

o-Phthalaldehyde

PTZ:

Pentylenetetrazole

RNA:

Ribonucleic acid

SEM:

Standard error of mean

SOD:

Superoxide dismutase

UV:

Ultraviolet spectroscopy

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Acknowledgments

The authors greatly acknowledge M/s Vittarthaa Life Sciences, Bommasandra Industrial Area, Bangalore for providing required facilities to carry out the research work.

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Authors and Affiliations

  1. Bangalore, India

    Gollapalle Lakshminarayanashastry Viswanatha & Hanumanthappa Shylaja

  2. Shadan College of Pharmacy. (SCOP) Peerancheru, Hyderabad, 500086, India

    Darisi Venkata Kishore

  3. Connexios Life Sciences Pvt Ltd, Basavanagudi, Bangalore, 560 004, India

    Marikunte V. Venkataranganna

  4. Oil Technological and Pharmaceutical Research Institute (OTPRI), JNT University Anantapur, Ananthapuramu, 515 002, India

    Nunna Bheema Lingeswara Prasad

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  1. Gollapalle Lakshminarayanashastry Viswanatha
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  3. Darisi Venkata Kishore
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  4. Marikunte V. Venkataranganna
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  5. Nunna Bheema Lingeswara Prasad
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Contributions

GLV, HS, DVK, MVV, and NBLP have contributed equally in the designing and conducting the study, data collection, analysis, and preparation of the manuscript. MVV and NBLP were involved in the critical analysis and interpretation of findings. HS and NBLP have proofread and approved the final version of the manuscript.

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Viswanatha, G.L., Shylaja, H., Kishore, D.V. et al. Acteoside Isolated from Colebrookea oppositifolia Smith Attenuates Epilepsy in Mice Via Modulation of Gamma-Aminobutyric Acid Pathways. Neurotox Res 38, 1010–1023 (2020). https://doi.org/10.1007/s12640-020-00267-0

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