Anti-epileptic effect of 16-O-acetyldigitoxigenin via suppressing mTOR signaling pathway

Wenjing Tu; Sheng Qian

doi:10.14715/cmb/2019.65.5.10

Issue

Vol. 65 No. 5: Issue 5

Issue Published : July 13, 2019

The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.

Anti-epileptic effect of 16-O-acetyldigitoxigenin via suppressing mTOR signaling pathway

https://doi.org/10.14715/cmb/2019.65.5.10

Wenjing Tu

Department of Neurology, Wuhan Women and Children Health Care Center, Wuhan 430000, Hubei Province, China

Sheng Qian

Department of Surgery, Wuhan Xincheng Hospital, Wuhan 430000, Hubei Province, China

Corresponding Author(s) : Wenjing Tu

ddcie5@163.com

Cellular and Molecular Biology, Vol. 65 No. 5: Issue 5
Article Published : June 30, 2019

Abstract

Epilepsy is a common chronic disease of the central nervous system that can last for years or even decades, causing serious adverse effects on the body, mind, and psychology of patients. Traditional antiepileptic drugs can effectively control seizures, but because of large individual differences, serious adverse reactions, narrow therapeutic window and other shortcomings, more effective, new treatment drugs are looked for. Streptocaulon griffithii is a plant of Asclepiadaceae. 16-O-acetyldigitoxigenin (ACE) is a strong cardiac glycoside isolated from methanol extract of Streptocaulon griffithii. The aim of this study was to investigate the antiepileptic effect of ACE on Pilocarpine (Pilo) induced epilepsy in mice, and to explore the effect of mTOR signaling pathway on its antiepileptic effect. The results showed that ACE had antiepileptic and neuroprotective effects on Pilo induced epilepsy mice. ACE attenuates Pilo induced seizures by inhibiting the activation of p-mTOR/p-70S6K pathway, and inhibits Pilocarpine induced brain damage by inhibiting mTOR signaling pathway. These results suggest that ACE has a promising future in the treatment of epilepsy and other nervous system diseases.

Keywords

Streptocaulon juventas Anti-epileptic 16-O-acetyldigitoxigenin mTOR.

Tu, W., & Qian, S. (2019). Anti-epileptic effect of 16-O-acetyldigitoxigenin via suppressing mTOR signaling pathway. Cellular and Molecular Biology, 65(5), 59–63. https://doi.org/10.14715/cmb/2019.65.5.10

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References

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Cho CH. New mechanism for glutamate hypothesis in epilepsy. Front Cell Neurosci 2013; 7: 127.
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Xue R, Han N, Xia M, Ye C, Hao Z, Wang L, et al. TXA9, a cardiac glycoside from Streptocaulon juventas, exerts a potent anti-tumor activity against human non-small cell lung cancer cells in vitro and in vivo. Steroids 2015; 94: 51-59.
Xue R, Han N, Ye C, Wang HB, Yin J. Cardenolide glycosides from root of Streptocaulon juventas. Phytochemistry 2013; 88: 105-111.
Klitgaard H, Matagne A, Vannestegoemaere J, Margineanu D. Pilocarpine-induced epileptogenesis in the rat: impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations. Epilepsy Res 2002; 51: 93-107.
Proper EA, Jansen GH, van Veelen CW, van Rijen PC, Gispen WH, de Graan P. A grading system for hippocampal sclerosis based on the degree of hippocampal mossy fiber sprouting. Acta Neuropathol 2001; 101: 405-409.
Yang X, Yang C, Farberman A, Rideout TC, de Lange CF, France J, et al. The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth. J Anim Sci 2008; 86: 36.
Yuan RR, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009; 2: 45.
Henna H, Anni N, Matti S, Anne K, Juha K, Sampsa H, et al. Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer. BMC Genomics 2008; 9: 348-348.
Lafaychebassier C, Paccalin M, Page G, Barcpain S, Peraultpochat MC, Gil R, et al. mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. J Neurochem 2010; 94: 215-225.
Jiang TF, Zhang YJ, Zhou HY, Wang HM, Tian LP, Liu J, et al. Curcumin Ameliorates the Neurodegenerative Pathology in A53T Î±-synuclein Cell Model of Parkinson's Disease Through the Downregulation of mTOR/p70S6K Signaling and the Recovery of Macroautophagy. J Neuroimmune Pharmacol 2013; 8: 356-369.
Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 2010; 40: 193-199.
Maiese K, Chong ZZ, Shang YC, Wang S. mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med 2013; 19: 51-60.
Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 2009; 29: 6964-6972.
LaSarge CL, Danzer SC. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci 2014; 7: 18.
Vezzani A, Balosso S, Ravizza T. The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 2008; 22: 797-803.

References

Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B, et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol 2010; 136: 659-672.

Cho CH. New mechanism for glutamate hypothesis in epilepsy. Front Cell Neurosci 2013; 7: 127.

Lerche H, Jurkat RK, Lehmannhorn F. Ion channels and epilepsy. Am J Med Genet A 2001; 106: 146-159.

Fang M, Xi ZQ, Wu Y, Wang XF. A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses 2011; 76: 871-876.

Costa C, Prontera P, Sarchielli P, Tonelli A, Bassi MT, Cupini LM, et al. A novel ATP1A2 gene mutation in familial hemiplegic migraine and epilepsy. Cephalalgia 2014; 34: 68-72.

Rogawski MA, Tofighy A, White HS, Matagne A, Wolff C. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res 2015; 110: 189-205.

Zhao Q, Chen X, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull (Beijing) 2016; 61: 1391-1398.

Garba K, Yaro AH, Ya'U J. Anticonvulsant effects of ethanol stem bark extract of Lannea barteri (Anacardiaceae) in mice and chicks. J Ethnopharmacol 2015; 172: 227-231.

Carla M, Paola G, Stafford GI, Johannes VS. South African plants used in traditional medicine to treat epilepsy have an antagonistic effect on NMDA receptor currents. J Ethnopharmacol 2011; 137: 382-388.

Ueda JY, Tezuka Y, Banskota AH, Tran QL, Tran QK, Saiki I, et al. Constituents of the Vietnamese medicinal plant Streptocaulon juventas and their antiproliferative activity against the human HT-1080 fibrosarcoma cell line. J Nat Prod 2003; 66: 1427-1433.

Ueda JY, Tezuka Y, Banskota AH, Le TQ, Tran QK, Harimaya Y, et al. Antiproliferative activity of Vietnamese medicinal plants. Biol Pharm Bull 2002; 25: 753-760.

Xue R, Han N, Xia M, Ye C, Hao Z, Wang L, et al. TXA9, a cardiac glycoside from Streptocaulon juventas, exerts a potent anti-tumor activity against human non-small cell lung cancer cells in vitro and in vivo. Steroids 2015; 94: 51-59.

Xue R, Han N, Ye C, Wang HB, Yin J. Cardenolide glycosides from root of Streptocaulon juventas. Phytochemistry 2013; 88: 105-111.

Klitgaard H, Matagne A, Vannestegoemaere J, Margineanu D. Pilocarpine-induced epileptogenesis in the rat: impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations. Epilepsy Res 2002; 51: 93-107.

Proper EA, Jansen GH, van Veelen CW, van Rijen PC, Gispen WH, de Graan P. A grading system for hippocampal sclerosis based on the degree of hippocampal mossy fiber sprouting. Acta Neuropathol 2001; 101: 405-409.

Yang X, Yang C, Farberman A, Rideout TC, de Lange CF, France J, et al. The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth. J Anim Sci 2008; 86: 36.

Yuan RR, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009; 2: 45.

Henna H, Anni N, Matti S, Anne K, Juha K, Sampsa H, et al. Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer. BMC Genomics 2008; 9: 348-348.

Lafaychebassier C, Paccalin M, Page G, Barcpain S, Peraultpochat MC, Gil R, et al. mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. J Neurochem 2010; 94: 215-225.

Jiang TF, Zhang YJ, Zhou HY, Wang HM, Tian LP, Liu J, et al. Curcumin Ameliorates the Neurodegenerative Pathology in A53T Î±-synuclein Cell Model of Parkinson's Disease Through the Downregulation of mTOR/p70S6K Signaling and the Recovery of Macroautophagy. J Neuroimmune Pharmacol 2013; 8: 356-369.

Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 2010; 40: 193-199.

Maiese K, Chong ZZ, Shang YC, Wang S. mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med 2013; 19: 51-60.

Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 2009; 29: 6964-6972.

LaSarge CL, Danzer SC. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci 2014; 7: 18.

Vezzani A, Balosso S, Ravizza T. The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 2008; 22: 797-803.

Author biographies is not available.