Nat Prod Sci.  2017 Mar;23(1):40-45. 10.20307/nps.2017.23.1.40.

Protection Against Electroshock- and Pentylenetetrazol-induced Seizures by the Water Extract of Rehmannia glutinous can be Mediated through GABA Receptor-chloride Channel Complexes

• Kim M
• Kim HJ
• Kim SM
• De la Peña JB
• Dela Peña IJ
• Botanas CJ
• Woo T
• Lee YS
• Ryu JH
• Cheong JH

• KMID: 2376498
• DOI: http://doi.org/10.20307/nps.2017.23.1.40

Abstract

Epilepsy is a brain disorder that affects millions of people worldwide. It is characterized by recurrent and unpredictable seizures that are usually controlled with antiepileptic/anticonvulsive drugs. However, most antiepileptic drugs produce various side effects such as tolerance and sedation. Thus, there is a growing interest for alternative anticonvulsive drugs, preferably from natural or herbal sources. In this study, we evaluated the anticonvulsive effects of Rehmannia glutinosa (RG). The anticonvulsive effect of RG extract was evaluated using electroshock- and chemical-induced seizure tests in mice. To identify its probable mechanism of action, the effects of RG extract on Cl− influx was measured in vitro. We found that RG extract has anticonvulsive effects against electroshock-induced seizures, as indicated by an increased seizure threshold in mice. The RG extract also decreased the percentage of seizure responses induced by the GABAergic antagonist, pentylenetetrazole. These results suggest that the anticonvulsive effects of RG extract are mediated through a GABAergic mechanism. In support of this mechanism, our in vitro test showed that RG extract increases intracellular Cl− influx. Furthermore, RG extract did not show sedative and/or muscle relaxant effects in the open-field and rota-rod tests. Altogether, these results confirm that RG extract could be a herbal anticonvulsant and a potential alternative for clinical use.

Keyword

Rehmannia glutinosa; Anticonvulsant; Epilepsy; GABA; Electroshock-induced seizure; Chemical-induced seizure

MeSH Terms

Animals
Anticonvulsants
Brain Diseases
Epilepsy
gamma-Aminobutyric Acid*
In Vitro Techniques
Mice
Pentylenetetrazole
Rehmannia*
Seizures*
Water*
Anticonvulsants
Pentylenetetrazole
Water
gamma-Aminobutyric Acid

Figure

• 

  Fig. 1. Effects of Rehmannia glutinosa (RG) water extract and ethanol extract on seizures induced by electroshock in animals (n = 10 per group). The numbers in the box represent CC50 ± 95% confidence intervals (∗p < 0.05 versus control; ∗∗p < 0.01 versus control; DZP, diazepam).

• 

  Fig. 2. Effects of RG water extract on seizures induced by electroshock in animals (n = 20 per group). The numbers in the box represent CC50 ± 95% confidence intervals (∗p < 0.05 versus control; ∗∗p < 0.01 versus control; DZP, diazepam).

• 

  Fig. 3. Effects of RG water extract on seizures induced by PTZ in animals (n = 15 per group). Each bar represents mean ± SEM of percent seizure response (∗p < 0.05 versus control; ∗∗∗p < 0.001 versus control; DZP, diazepam).

• 

  Fig. 4. Effects of RG water extract on seizures induced by strychnine in animals (n = 12 − 14 per group). Each barrepresents mean ± SEM of percent seizure response (∗∗∗p < 0.001 versus control; DZP, diazepam).

• 

  Fig. 5. Effects of RG water extract on Cl− influx in neuroblastoma cells. Fluorescence was monitored with an excitation wavelength of 365 nm and an emission wavelength of 450 nm, using the Cl−-sensitive indicator, N-(methoxyquinolyl) acetoety-lester (MAQE). Contents of influx Cl− ion were expressed as a peak (a.u.).

• 

  Fig. 6. Effects of RG water extract on locomotor activity in animals (n = 10 per group). Each bar represents mean ± SEM of total distance moved (A) and the movement duration (B) for 10 min (∗∗∗p < 0.001 versus control; DZP, diazepam).

• 

  Fig. 7. Effects of RG water extract on the rota-rod test in animals (n = 10 per group). Each bar represents mean ± SEM of the latency time (A) and falling frequency (B) for 10 min (∗∗ p < 0.01 versus control; ∗∗∗p < 0.001 versus control; DZP, diazepam).

Reference

References

(1). Fisher R.S.., van Emde Boas W.., Blume W.., Elger C.., Genton P.., Lee P.., Engel Jr J.Epilepsia. 2005. 46:470–472.

(2). Blume W.T.., Lüders H.O.., Mizrahi E.., Tassinari C.., van Emde Boas W.., Engel Jr J.Epilepsia. 2001. 42:1212–1218.

(3). Shorvon S.Handbook of epilepsy treatment (3rd ed); John Wiley & Sons: United Kingdom,. 2010.

(4). Schmidt D.., Schachter S.C.BMJ. 2014. 348:g254.

(5). Swann A.C. J.Clin. Psychiatry. 2001. 62:16–21.

(6). Megiddo I.., Colson A.., Chisholm D.., Dua T.., Nandi A.., Laxminarayan R.Epilepsia. 2016. 57:464–474.

(7). Samuels N.., Finkelstein Y.., Singer S.R.., Oberbaum M.Epilepsia. 2008. 49:373–380.

(8). QuintansJúnior L.J.., Almeida J.R.., Lima J.T.., Nunes X.P.., Siqueira J.S.., Oliveira L.E.G.., Almeida R.N.., Athayde-Filho P.F.., Barbosa-Filho J.M.Rev. Bras. Farmacogn. 2008. 18:798–819.

(9). Woo T.S.., Yoon S.Y.., dela Peña I.C.., Choi J.Y.., Lee H.L.., Choi Y.J.., Lee Y.S.., Ryu J.H.., Choi J.S.., Cheong J.H.Biomol. Ther. 2011. 19:342–347.

(10). Hijikata Y.., Yasuhara A.., Yoshida Y.., Sento S. J.Altern. Complement. Med. 2006. 12:673–677.

(11). Kwon B.H.., Gu B.S. J.Oriental Neuropsychiatry,. 1999. 10:1–27.

(12). Jiao Z.., Cheng Y.., Wang H.., Lei C.., Wang G.G.., Han L.Appl. Plant Sci. 2015. 3:1500054.

(13). Baek G.H.., Jang Y.S.., Jeong S.I.., Cha J.., Joo M.., Shin S.W.., Ha K.T.., Jeong H. S.Inflammation. 2012. 35:1232–1241.

(14). Dingding C.., Dai Dezai Z. T.Pharmacology and Clinics of Chinese Materia Medica. 1996. 5:010.

(15). Huang Y.., Jiang C.., Hu Y.., Zhao, X.;Shi C.., Yu Y.., Liu C.., Tao Y.., Pan H.., Feng Y.., Liu J.., Wu Y.., Wang D.Carbohydr. Polym. 2013. 96:516–521.

(16). Kim H.M.; An, C.S.; Jung, K.Y.; Choo, Y.K.; Park, J.K.; Nam, S.Y. Pharmacol. Res. 1999. 40:171–176.

(17). Kim S.S.; Son, Y.O.; Chun, J.C.; Kim, S.E.; Chung, G.H.; Hwang, K.J.; Lee, J.C. Redox. Rep. 2005. 10:311–318.

(18). Wang Y.B.., Liu Y.F.., Lu X.T.., Yan F.F.., Wang B.., Bai W.W.., Zhao Y.X.PLoS One. 2013. 8:, e54303.

(19). Yuan Y.., Hou S.., Lian T.., Han Y.Zhongguo Zhong Yao Za Zhi. 1992. 17:366–368.

(20). Zhang R.X.., Li M.X.., Jia Z.P. J.Ethnopharmacol. 2008. 117:199–214.

(21). Yoon S.Y.., dela Peña I.C.., Shin C.Y.., Son K.H.., Lee Y.S.., Ryu J.H.., Cheong, J.H.;Ko K.H.Eur. J. Pharmacol. 2011. 659:155–160.

(22). Pellmar T. C.., Wilson W.A.Science. 1977. 197:912–914.

(23). Larson A.A.., Beitz A. J. J.Neurosci. 1988. 8:3822–3826.

(24). West M. R.., Molloy C. R.Anal. Biochem. 1996. 241:51–58.

(25). Löscher W.., Fassbender C. P.., Nolting B.Epilepsy Res. 1991. 8:79–94.

(26). Rogawski M.A.., Porter R.J.Pharmacol. Rev. 1990. 42:222–286.

(27). De Deyn P.P.., Marescau B.., MacDonald R.L.Acta Neurol. Belg. 1989. 90:65–81.

(28). Lynch J.W.Physiol. Rev. 2004. 84:1051–1095.

(29). Young A.B.., Zukin S.R.., Snyder S.H.Proc. Natl. Acad. Sci. U.S.A. 1974. 71:2246–2250.

(30). Rho J.M.., Donevan S.D.., Rogawski M.A.Ann. Neurol. 1994. 35:229–234.

(31). Crestani F.., Löw K.., Keist R.., Mandelli M.J.., Möhler H.., Rudolph U.Mol. Pharmacol. 2001. 59:442–445.

(32). McBurney R.N.., Barker J. L.Nature. 1978. 274:596–597.