Skip to main content

Advertisement

Log in

Protective Effects of Thymoquinone Against Convulsant Activity Induced by Lithium-Pilocarpine in a model of Status Epilepticus

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Inflammation plays a pivotal role in status epilepticus (SE). Thymoquinone (TQ) is a bioactive monomer extracted from black seed (Nigella sativa) oil, which has anti-inflammatory properties in the context of various diseases. This study explored the protective effects of TQ in SE and used a lithium-pilocarpine model of SE to investigate the underlying mechanism, which was related to inflammation mediated by the NF-κB signaling pathway. In the present study, latency to SE increased in the TQ-pretreated group compared with the SE group, and the incidence of SE was significantly reduced. The seizure severity score measured on the Racine scale was significantly decreased in the TQ group compared with the SE group. Moreover, the results of the behavioral tests suggested that TQ may also have a protective effect on learning and memory functions. Finally, we further investigated the protective mechanism of TQ. The results showed that TQ-pretreatment significantly downregulated the protein levels of COX-2 and TNF-α in the brain, in a manner mediated by the NF-κB signaling pathway. These findings demonstrate that TQ attenuates convulsant activity via an anti- inflammation signaling pathway in a model of SE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Akhondian J, Kianifar H, Raoofziaee M, Moayedpour A, Toosi MB, Khajedaluee M (2010) The effect of thymoquinone on intractable pediatric seizures (pilot study). Epilepsy Res 93:39–43. doi:10.1016/j.eplepsyres.2010.10.010

    Article  PubMed  Google Scholar 

  2. Alyoussef A, Al-Gayyar MM (2016) Thymoquinone ameliorated elevated inflammatory cytokines in testicular tissue and sex hormones imbalance induced by oral chronic toxicity with sodium nitrite. Cytokine 83:64–74. doi:10.1016/j.cyto.2016.03.018

    Article  CAS  PubMed  Google Scholar 

  3. Aronica E, Ravizza T, Zurolo E, Vezzani A (2012) Astrocyte immune response in epilepsy. Glia 60:1258–1268. doi:10.1002/glia.22312

    Article  PubMed  Google Scholar 

  4. Banerjee S, Padhye S, Azmi A, Wang Z, Philip PA, Kucuk O, Sarkar FH, Mohammad RM (2010) Review on molecular and therapeutic potential of thymoquinone in cancer. Nutr Cancer 62:938–946. doi:10.1080/01635581.2010.509832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen L, Yang X, Zhou X, Wang C, Gong X, Chen B, Chen Y (2015) Hyperactivity and impaired attention in Gamma aminobutyric acid transporter subtype 1 gene knockout mice. Acta Neuropsychiatr 27:368–374. doi:10.1017/neu.2015.37

    Article  PubMed  Google Scholar 

  6. Choi J, Nordli DR Jr, Alden TD, DiPatri A Jr, Laux L, Kelley K, Rosenow J, Schuele SU, Rajaram V, Koh S (2009) Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflamm 6:38. doi:10.1186/1742-2094-6-38

    Article  Google Scholar 

  7. Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S (2015) Thymoquinone and its therapeutic potentials. Pharmacol Res 95–96:138–158. doi:10.1016/j.phrs.2015.03.011

    Article  PubMed  Google Scholar 

  8. De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani, A (2000) Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 12:2623–2633

    Article  PubMed  Google Scholar 

  9. Dham BS, Hunter K, Rincon F (2014) The epidemiology of status epilepticus in the United States. Neurocrit Care 20:476–483. doi:10.1007/s12028-013-9935-x

    Article  PubMed  Google Scholar 

  10. Gökce EC, Kahveci R, Gökce A, Cemil B, Aksoy N, Sargon MF, Kısa, Ü., Erdoğan B, Güvenç Y, Alagöz F, Kahveci O (2016) Neuroprotective effects of thymoquinone against spinal cord ischemia–reperfusion injury by attenuation of inflammation, oxidative stress, and apoptosis. J Neurosurg Spine 12:1–11. doi:10.3171/2015.10.SPINE15612

    Google Scholar 

  11. Hadera MG, Faure JB, Berggaard N, Tefera TW, Nehlig A, Sonnewald U (2014) The anticonvulsant actions of carisbamate associate with alterations in astrocyte glutamine metabolism in thelithium-pilocarpine epilepsy model. J Neurochem 132:532–545. doi:10.1111/jnc.12977

    PubMed  Google Scholar 

  12. Hosseinzadeh H, Parvardeh S, Nassiri-Asl M, Mansouri MT (2011) Intracerebroventricular administration of thymoquinone, the major constituent of Nigella sativa seeds, suppresses epileptic seizures in rats. Med Sci Monit 11:BR106–B110

    Google Scholar 

  13. Jiang J, Yang MS, Quan Y, Gueorguieva P, Dingledine R (2015) Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol Dis 76:126–136. doi:10.1016/j.neuropharm.2015.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, Katsarou N, Hamer HM (2001) Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 42:714–718

    Article  CAS  PubMed  Google Scholar 

  15. Lehmann J, Weizman R, Pryce CR, Leschiner S, Allmann I, Feldon J, Gavish M (1999) Peripheral benzodiazepine receptors in cerebral cortex, but not in internal organs, are increased following inescapable stress and subsequent avoidance/escape shuttle-box testing. Brain Res 851:141–147

    Article  CAS  PubMed  Google Scholar 

  16. Ma L, Cui XL, Wang Y, Li XW, Yang F, Wei D, Jiang W (2012) Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res 1469:103–113. doi:10.1016/j.brainres.2012.05.058

    Article  CAS  PubMed  Google Scholar 

  17. Meng XF, Tan L, Tan MS, Jiang T, Tan CC, Li MM, Wang HF, Yu JT (2014) Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-inducedstatus epilepticus. J Neuroinflamm 11:212. doi:10.1186/s12974-014-0212-5

    Article  Google Scholar 

  18. Morcos M, Schlotterer A, Sayed AA, Kukudov G, Oikomonou D, Ibrahim Y, Pfisterer F, Schneider J, Bozorgmehr F, Rudofsky G Jr, Schwenger V, Kientsch-Engels R, Hamann A, Zeier M, Dugi K, Yard B, Humpert PM, van der, Woude, F., Nawroth PP, Bierhaus A (2008) Rosiglitazone reduces angiotensin II and advanced glycation end product-dependent sustained nuclear factor-κB activation in cultured human proximal tubular epithelial cells. Horm Metab Res 40:752–759. doi:10.1055/s-0028-1082039

    Article  CAS  PubMed  Google Scholar 

  19. Racine RJ (1972) Modification of seizure activity by electrical stimulation: II motor seizure. J Electroenceph Clin Neurophysiol 32:281–294

    Article  CAS  Google Scholar 

  20. Rojas A, Ganesh T, Lelutiu N, Gueorguieva P (2015) Dingledine R. Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus. Neuropharmacology 93:15–27. doi:10.1016/j.neuropharm.2015.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shih RH, Wang CY, Yang CM (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8:77. doi:10.3389/fnmol.2015.00077

    Article  PubMed  PubMed Central  Google Scholar 

  22. Spatola M, Novy J, Du Pasquier R, Dalmau J, Rossetti AO (2015) Status epilepticus of inflammatory etiology: a cohort study. Neurology 85:464–470. doi:10.1212/WNL

    Article  PubMed  PubMed Central  Google Scholar 

  23. Su J, Yin J, Qin W, Sha S, Xu J, Jiang C (2015) Role for pro-inflammatory cytokines in regulating expression of GABA transporter type 1 and 3 in specific brain regions of kainic acid-induced status epilepticus. Neurochem Res 40:621–627. doi:10.1007/s11064-014-1504-y

    Article  CAS  PubMed  Google Scholar 

  24. Taka E, Mazzio EA, Goodman CB, Redmon N, Flores-Rozas H, Reams R, Darling-Reed S, Soliman KF (2015) Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells. J Neuroimmunol 286:5–12. doi:10.1016/j.jneuroim.2015.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Trinka E, Cock H, Hesdorffer D, Rossetti A, Scheffer IE, Shinnar S, Shorvon S, Lowenstein DH (2015) A definition and classification of status epilepticus-report of the ILAE task forceon classification of status epilepticus. Epilepsia 56:1515–1523. doi:10.1111/epi.13121

    Article  PubMed  Google Scholar 

  26. Ullah I, Badshah H, Naseer MI, Lee HY, Kim MO (2015) Thymoquinone and vitamin C attenuates pentylenetetrazole-induced seizures via activation of GABAB1 receptor in adult rats cortex and hippocampus. Neuromol Med 17:35–46. doi:10.1007/s12017-014-8337-3

    Article  CAS  Google Scholar 

  27. Vezzani A, Balosso S, Ravizza T (2008) The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 22:797–803. doi:10.1016/j.bbi.2008.03.009

    Article  CAS  PubMed  Google Scholar 

  28. Vezzani A, French J, Bartfai T, Baram TZ (2011). The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40. doi:10.1038/nrneurol.2010.178

    Article  CAS  PubMed  Google Scholar 

  29. Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24. doi:10.1016/j.neuropharm.2012.04.004

    Article  CAS  PubMed  Google Scholar 

  30. Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This investigation was supported by grants from the Traditional Chinese Medicine Research Fund of the Shanghai Municipal Commission of Health and Family Planning (2014JP007A) to YC.

Author Contributions

Y. Shao performed the western blot assays, generated the figures, and wrote the manuscript. Sihui Hu, Y. Feng and Q. Luo conducted the behavioral tests. Y. Xie and B. Li performed the electrophysiological procedures. Y. Chen contributed to the development of the project and the design and performance of the experiments. All of the authors have read and approved the final manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Bing Li or Yinghui Chen.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shao, Y., Feng, Y., Xie, Y. et al. Protective Effects of Thymoquinone Against Convulsant Activity Induced by Lithium-Pilocarpine in a model of Status Epilepticus. Neurochem Res 41, 3399–3406 (2016). https://doi.org/10.1007/s11064-016-2074-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-016-2074-y

Keywords

Navigation