Advertisement

Neurochemical Research

, Volume 44, Issue 4, pp 994–1004 | Cite as

2-Deoxy-d-Glucose Exhibits Anti-seizure Effects by Mediating the Netrin-G1-KATP Signaling Pathway in Epilepsy

  • Yuming Long
  • Kai Zhuang
  • Zhonghai Ji
  • Yaru Han
  • Yanqing Fei
  • Wen Zheng
  • Zhi SongEmail author
  • Heng YangEmail author
Original Paper
  • 73 Downloads

Abstract

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. The glycolytic inhibitor 2-deoxy-d-glucose (2-DG) has been reported to exert antiepileptic effects by upregulating KATP subunits (kir6.1 and kir6.2). We evaluated whether 2-DG exhibits anti-seizure effect by mediating the netrin-G1-KATP signaling pathway in epilepsy. In a mouse epilepsy model induced by lithium chloride-pilocarpine, 2-DG intervention increased the mRNA and protein expression levels of kir6.1 and kir6.2, and these increases were significantly reversed after knocking down netrin-G1 expression. Similarly, in cultured neurons with a magnesium-free medium, we found that the frequency of spontaneous postsynaptic potentials (SP) was increased, and in the meanwhile, expression levels of kir6.1 and kir6.2 were increased after pretreatment with 2DG. These effects were remarkably reversed after knocking down netrin-G1. Thus, our findings show that 2DG exhibits anti-seizure effects through the netrin-G1-KATP signaling pathway.

Keywords

Epilepsy Netrin-G1 KATP 2DG 

Notes

Acknowledgements

The work was supported by the National Natural Science Foundation of China (81501128) and National Natural Science Foundation of China (81671296). The Jiyizhupao of Third Xiangya Hospital (JY201520). Thanks to the Experimental Animal Center of the Third Xiangya Hospital of Central South University for affording animals.

Author Contributions

Yuming Long and Kai Zhuang were both the first author to this article. Heng Yang and Zhi Song were both the corresponding author to this article. Yuming Long and Kai Zhuang conducted all the experiments and drafed the main manuscript text. Zhonghai Ji, Yaru Han, Yanqing Fei and Wen Zheng made statistical analysis and prepared all the figures in this article. Heng Yang and Zhi Song designed the whole experiment procedure and supervised the research.

Compliance with Ethical Standards

Conflict of interest

The authors have declared that no competing interests exist.

References

  1. 1.
    Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE et al (2014) ILAE official report: a practical clinical definition of epilepsy. EPILEPSIA 55:475–482CrossRefGoogle Scholar
  2. 2.
    Tanywe A, Matchawe C, Fernandez R (2016) The experiences of people living with epilepsy in developing countries: a systematic review of qualitative evidence. JBI Database System Rev Implement Rep 14:136–192CrossRefGoogle Scholar
  3. 3.
    Nadler JV (2003) The recurrent mossy fiber pathway of the epileptic brain. Neurochem Res 28:1649–1658CrossRefGoogle Scholar
  4. 4.
    Pan Y, Liu G, Fang M, Shen L, Wang L, Han Y et al (2010) Abnormal expression of netrin-G2 in temporal lobe epilepsy neurons in humans and a rat model. Exp Neurol 224:340–346CrossRefGoogle Scholar
  5. 5.
    Yin Y, Miner JH, Sanes JR (2002) Laminets: laminin- and netrin-related genes expressed in distinct neuronal subsets. Mol Cell Neurosci 19:344–358CrossRefGoogle Scholar
  6. 6.
    Moore SW, Tessier-Lavigne M, Kennedy TE (2007) Netrins and their receptors. Adv Exp Med Biol 621:17–31CrossRefGoogle Scholar
  7. 7.
    Meerabux JM, Ohba H, Fukasawa M, Suto Y, Aoki-Suzuki M, Nakashiba T et al (2005) Human netrin-G1 isoforms show evidence of differential expression. GENOMICS 86:112–116CrossRefGoogle Scholar
  8. 8.
    Nakashiba T, Ikeda T, Nishimura S, Tashiro K, Honjo T, Culotti JG et al (2000) Netrin-G1: a novel glycosyl phosphatidylinositol-linked mammalian netrin that is functionally divergent from classical netrins. J Neurosci 20:6540–6550CrossRefGoogle Scholar
  9. 9.
    Lin JC, Ho WH, Gurney A, Rosenthal A (2003) The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons. Nat Neurosci 6:1270–1276CrossRefGoogle Scholar
  10. 10.
    Kim S, Burette A, Chung HS, Kwon SK, Woo J, Lee HW et al (2006) NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation. Nat Neurosci 9:1294–1301CrossRefGoogle Scholar
  11. 11.
    Aoki-Suzuki M, Yamada K, Meerabux J, Iwayama-Shigeno Y, Ohba H, Iwamoto K et al (2005) A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia. Biol Psychiatry 57:382–393CrossRefGoogle Scholar
  12. 12.
    Medina-Ceja L, Pardo-Pena K, Ventura-Mejia C (2014) Evaluation of behavioral parameters and mortality in a model of temporal lobe epilepsy induced by intracerebroventricular pilocarpine administration. Neuroreport.  https://doi.org/10.1097/WNR.0000000000000207 Google Scholar
  13. 13.
    Woo J, Kwon SK, Kim E (2009) The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. Mol Cell Neurosci 42:1–10CrossRefGoogle Scholar
  14. 14.
    Ohtsuki T, Horiuchi Y, Koga M, Ishiguro H, Inada T, Iwata N et al (2008) Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations. Neurosci Lett 435:194–197CrossRefGoogle Scholar
  15. 15.
    Eastwood SL, Harrison PJ (2008) Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. Neuropsychopharmacol 33:933–945CrossRefGoogle Scholar
  16. 16.
    Zakharyan R, Boyajyan A, Arakelyan A, Gevorgyan A, Mrazek F, Petrek M (2011) Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population. Hum Immunol 72:746–748CrossRefGoogle Scholar
  17. 17.
    Zhu Y, Yang H, Bi Y, Zhang Y, Zhen C, Xie S et al (2011) Positive association between NTNG1 and schizophrenia in Chinese Han population. J Genet 90:499–502CrossRefGoogle Scholar
  18. 18.
    Stepanyan A, Zakharyan R, Boyajyan A (2013) The netrin G1 gene rs628117 polymorphism is associated with ischemic stroke. Neurosci Lett 549:74–77CrossRefGoogle Scholar
  19. 19.
    Foster MN, Coetzee WA (2016) KATP channels in the cardiovascular system. Physiol Rev 96:177–252CrossRefGoogle Scholar
  20. 20.
    Zhou M, Tanaka O, Suzuki M, Sekiguchi M, Takata K, Kawahara K et al (2002) Localization of pore-forming subunit of the ATP-sensitive K(+)-channel, Kir6.2, in rat brain neurons and glial cells. Brain Res Mol Brain Res 101:23–32CrossRefGoogle Scholar
  21. 21.
    Wickenden AD (2002) Potassium channels as anti-epileptic drug targets. Neuropharmacology 43:1055–1060CrossRefGoogle Scholar
  22. 22.
    Yang H, Guo R, Wu J, Peng Y, Xie D, Zheng W et al (2013) The antiepileptic effect of the glycolytic inhibitor 2-deoxy-D-glucose is mediated by upregulation of K(ATP) channel subunits Kir6.1 and Kir6.2. Neurochem Res 38:677–685CrossRefGoogle Scholar
  23. 23.
    McIntyre DC, Poulter MO, Gilby K (2002) Kindling: some old and some new. Epilepsy Res 50:79–92CrossRefGoogle Scholar
  24. 24.
    Raedt R, Van Dycke A, Van Melkebeke D, De Smedt T, Claeys P, Wyckhuys T et al (2009) Seizures in the intrahippocampal kainic acid epilepsy model: characterization using long-term video-EEG monitoring in the rat. Acta Neurol Scand 119:293–303CrossRefGoogle Scholar
  25. 25.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408CrossRefGoogle Scholar
  26. 26.
    Rutecki PA, Lebeda FJ, Johnston D (1985) Epileptiform activity induced by changes in extracellular potassium in hippocampus. J Neurophysiol 54:1363–1374CrossRefGoogle Scholar
  27. 27.
    Traynelis SF, Dingledine R (1988) Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol 59:259–276CrossRefGoogle Scholar
  28. 28.
    Traynelis SF, Dingledine R, McNamara JO, Butler L, Rigsbee L (1989) Effect of kindling on potassium-induced electrographic seizures in vitro. Neurosci Lett 105:326–332CrossRefGoogle Scholar
  29. 29.
    Tancredi V, Hwa GG, Zona C, Brancati A, Avoli M (1990) Low magnesium epileptogenesis in the rat hippocampal slice: electrophysiological and pharmacological features. Brain Res 511:280–290CrossRefGoogle Scholar
  30. 30.
    Sombati S, Delorenzo RJ (1995) Recurrent spontaneous seizure activity in hippocampal neuronal networks in culture. J Neurophysiol 73:1706–1711CrossRefGoogle Scholar
  31. 31.
    Clark S, Wilson WA (1999) Mechanisms of epileptogenesis. Adv Neurol 79:607–630Google Scholar
  32. 32.
    Gasior M, Yankura J, Hartman AL, French A, Rogawski MA (2010) Anticonvulsant and proconvulsant actions of 2-deoxy-d-glucose. Epilepsia 51:1385–1394CrossRefGoogle Scholar
  33. 33.
    Matsukawa H, Akiyoshi-Nishimura S, Zhang Q, Lujan R, Yamaguchi K, Goto H et al (2014) Netrin-G/NGL complexes encode functional synaptic diversification. J Neurosci 34:15779–15792CrossRefGoogle Scholar
  34. 34.
    Jiang K, Shui Q, Xia Z, Yu Z (2004) Changes in the gene and protein expression of K(ATP) channel subunits in the hippocampus of rats subjected to picrotoxin-induced kindling. Brain Res Mol Brain Res 128:83–89CrossRefGoogle Scholar
  35. 35.
    Jiang KW, Gao F, Shui QX, Yu ZS, Xia ZZ (2004) Effect of diazoxide on regulation of vesicular and plasma membrane GABA transporter genes and proteins in hippocampus of rats subjected to picrotoxin-induced kindling. Neurosci Res 50:319–329CrossRefGoogle Scholar
  36. 36.
    Gimenez-Cassina A, Martinez-Francois JR, Fisher JK, Szlyk B, Polak K, Wiwczar J et al (2012) BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron 74:719–730CrossRefGoogle Scholar
  37. 37.
    He XP, Pan E, Sciarretta C, Minichiello L, McNamara JO (2010) Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis. J Neurosci 30:6188–6196CrossRefGoogle Scholar
  38. 38.
    Aziz Q, Thomas AM, Khambra T, Tinker A (2012) Regulation of the ATP-sensitive potassium channel subunit, Kir6.2, by a Ca2+-dependent protein kinase C. J Biol Chem 287:6196–6207CrossRefGoogle Scholar
  39. 39.
    Shi Y, Cui N, Shi W, Jiang C (2008) A short motif in Kir6.1 consisting of four phosphorylation repeats underlies the vascular KATP channel inhibition by protein kinase C. J Biol Chem 283:2488–2494CrossRefGoogle Scholar
  40. 40.
    Park WS, Ko EA, Han J, Kim N, Earm YE (2005) Endothelin-1 acts via protein kinase C to block KATP channels in rabbit coronary and pulmonary arterial smooth muscle cells. J Cardiovasc Pharmacol 45:99–108CrossRefGoogle Scholar
  41. 41.
    Wierda KD, Toonen RF, de Wit H, Brussaard AB, Verhage M (2007) Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron 54:275–290CrossRefGoogle Scholar
  42. 42.
    Forte N, Medrihan L, Cappetti B, Baldelli P, Benfenati F. 2-Deoxy-d-glucose enhances tonic inhibition through the neurosteroid-mediated activation of extrasynaptic GABAA receptors. Epilepsia 2016Google Scholar
  43. 43.
    Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM et al (2006) 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci 9:1382–1387CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurologyThe Third Xiangya Hospital of Central South UniversityChangshaPeople’s Republic of China
  2. 2.Department of NeurosurgeryThe Third Xiangya Hospital of Central South UniversityChangshaPeople’s Republic of China

Personalised recommendations