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Anticonvulsant and Neuroprotective Effects of Paeonol in Epileptic Rats

  • Dong-Hai Liu
  • Elvis Agbo
  • Shu-Hong Zhang
  • Jin-Ling ZhuEmail author
Original Paper
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Abstract

Paeonol is the main active compound in the root bark extract of the peony tree, and it has antioxidative and anti-inflammatory effects. Recent studies have reported the neuroprotective effects of paeonol including its capacity in improving impaired memory. However, the effect of paeonol on epilepsy is yet to be demystified. We aimed to investigate the therapeutic effect of paeonol in epilepsy and its relationship with oxidative stress damage and neuronal loss in the rat brain to reveal the underlying mechanisms of epileptic seizures. A rat model for chronic epilepsy was established, and the seizure scores of the rats in different groups were recorded. The seizure duration and the seizure onset latency were used to evaluate the anticonvulsant effects of paeonol. Terminal deoxynucleotidyl transferase dUTP nick end-labeling staining, Nissl staining and H/E staining were used to evaluate the effects of paeonol on neuronal loss and apoptosis in epileptic rats. The colorimetric assessment of malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, catalase activity and total antioxidant capacity of paeonol were used in assessing paeonol’s effect on oxidative stress in epileptic rats. Evaluation of Caspase-3 mRNA and protein expression levels were determined using western blot and quantitative real-time (RT-q)PCR. In this study, we found that paeonol reduced the seizure scores of epileptic rats and attenuated the duration and onset latency of seizures. Paeonol can also increase the activities of total antioxidant capacity, SOD and catalase activity and reduce MDA content as well. This suggests that paeonol can improve the level of oxidative stress in rats. More significantly, paeonol can improve neuronal loss and apoptosis in epileptic rats. These results indicate that paeonol has anticonvulsant and neuroprotective effects in epileptic rats. This effect may be caused by reducing oxidative stress.

Keywords

Paeonol Epilepsy Oxidative stress Anticonvulsant Neuroprotective Apoptosis 

Notes

Acknowledgements

The authors of this manuscript are grateful to Jiamusi University in China for providing the facilities for this study.

Funding

This research was funded by the Heilongjiang Provincial Department of Education Research Fund (2017-KYYWF-0583) and Heilongjiang University Student Innovation Project (201810222017).

Compliance with Ethical Standards

Conflict of interest

We hereby declare no conflicts of interest.

References

  1. 1.
    Kwan P, Schachter SC, Brodie MJ (2011) Current concepts: drug-resistant epilepsy. N Engl J Med 365(10):919–926CrossRefGoogle Scholar
  2. 2.
    Löscher W, Klitgaard H, Twyman RE et al (2013) New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 12(10):757–776CrossRefGoogle Scholar
  3. 3.
    Mishra A, Goel RK (2015) Comparative behavioral and neurochemical analysis of phenytoin and valproate treatment on epilepsy induced learning and memory deficit: search for add on therapy. Metab Brain Dis 30(4):1–8CrossRefGoogle Scholar
  4. 4.
    Schmidt D (2002) The clinical impact of new antiepileptic drugs after a decade of use in epilepsy. Epilepsy Res 50(1–2):21–32CrossRefGoogle Scholar
  5. 5.
    Patel M (2004) Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med 37(12):1951–1962CrossRefGoogle Scholar
  6. 6.
    Xinjian Z, Jingde D, Bing H et al (2017) Neuronal nitric oxide synthase contributes to PTZ kindling epilepsy-induced hippocampal endoplasmic reticulum stress and oxidative damage. Front Cell Neurosci 11:377Google Scholar
  7. 7.
    Sreekanth P, Shaunik S, Sara S et al (2015) Seizure-induced oxidative stress in temporal lobe epilepsy. Biomed Res Int 2015:1–20Google Scholar
  8. 8.
    Rong Y, Doctrow SR, Tocco G et al (1999) EUK-134, a synthetic superoxide dismutase, and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proc Natl Acad Sci USA 96(17):9897–9902CrossRefGoogle Scholar
  9. 9.
    Pearson JN, Rowley S, Liang LP et al (2015) Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy. Neurobiol Dis 82:289–297CrossRefGoogle Scholar
  10. 10.
    Sudha K, Rao AV, Rao A (2001) Oxidative stress and antioxidants in epilepsy. Clin Chim Acta 303(1–2):19–24CrossRefGoogle Scholar
  11. 11.
    Das A, Belagodu A, Reiter RJ et al (2010) Cytoprotective effects of melatonin on C6 astroglial cells exposed to glutamate excitotoxicity and oxidative stress. J Pineal Res 45(2):117–124CrossRefGoogle Scholar
  12. 12.
    Nordberg J, Arner ES (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31:1287–1312CrossRefGoogle Scholar
  13. 13.
    Bannister JV, Bannister WH, Rotilio G (1987) Aspects of the structure, function, and applications of superoxide dismutas. Crit Rev Biochem Mol Biol 22(2):111–180CrossRefGoogle Scholar
  14. 14.
    Zelko IN, Mariani TJ, Folz RJ (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33(3):337–349CrossRefGoogle Scholar
  15. 15.
    Chelikani P, Fita I, Loewen PC (2004) Diversity of structures and properties among catalases. Cell Mol Life Sci 61(2):192–208CrossRefGoogle Scholar
  16. 16.
    Gurpreet G, Samiksha K, Neha K et al (2017) Effect of oxidative stress on ABC transporters: contribution to epilepsy pharmacoresistance. Molecules 22(3):365CrossRefGoogle Scholar
  17. 17.
    Pitkanen A, Sutula TP (2002) Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 1:173–181CrossRefGoogle Scholar
  18. 18.
    Kotloski R, Lynch M, Lauersdorf S et al (2002) Repeated brief seizures induce progressive hippocampal neuron loss and memory deficits. Prog Brain Res 135(95–110):2wGoogle Scholar
  19. 19.
    Zhang X, Cui SS, Wallace AE et al (2002) Relations between brain pathology and temporal lobe epilepsy. J Neurosci 22(14):6052–6061CrossRefGoogle Scholar
  20. 20.
    Sayin U, Osting S, Hagen J et al (2003) Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats. J Neurosci 23:2759–2768CrossRefGoogle Scholar
  21. 21.
    Liou AKF, Clark RS, Henshall DC et al (2003) To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways. Prog Neurobiol 69:103–142CrossRefGoogle Scholar
  22. 22.
    Bengzon J, Mohapel P, Ekdahl CT et al (2002) Neuronal apoptosis after brief and prolonged seizures. Prog Brain Res 135:111–119CrossRefGoogle Scholar
  23. 23.
    Zhang LH, Xiao PG, Huang Y (1996) Recent progresses in pharmacological and clinical studies of paeonol. Chin J Integr Tradit West Med 16(3):187–190Google Scholar
  24. 24.
    Zhu Y-P (1998) Chemistry, pharmacology and applications chinese materia medica. CRC Press, Boca RatonGoogle Scholar
  25. 25.
    Ding Y, Li Q, Xu Y et al (2016) Attenuating oxidative stress by paeonol protected against acetaminophen-induced hepatotoxicity in mice. PLoS ONE 11(5):e0154375CrossRefGoogle Scholar
  26. 26.
    Liu MH, Lin AH, Lee HF et al (2014) Paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling. Front Physiol 2014(2014):208–218Google Scholar
  27. 27.
    An Z, Hongfei W, Jian P et al (2015) Synthesis and evaluation of paeonol derivatives as, potential multifunctional agents for the treatment of Alzheimer’s disease. Molecules 20(1):1304–1318CrossRefGoogle Scholar
  28. 28.
    He X, Cai Q, Li J et al (2018) Involvement of brain-gut axis in treatment of cerebral infarction by β-asaron and paeonol. Neurosci Lett 666:78–84CrossRefGoogle Scholar
  29. 29.
    Shi X, Chen YH, Liu H et al (2016) Therapeutic effects of paeonol on methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson’s disease in mice. Mol Med Rep 14:2397–2404CrossRefGoogle Scholar
  30. 30.
    Liu Y, Wang T, Liu X et al (2018) Overexpression of zinc-α2-glycoprotein suppressed seizures and seizure-related neuroflammation in pentylenetetrazol-kindled rats. J Neuroinflammation 15(1):92CrossRefGoogle Scholar
  31. 31.
    Ojewole JA (2005) Analgesic and anticonvulsant properties of Tetrapleura tetraptera (Taub) (Fabaceae) fruit aqueous extract in mice. Phytother Res 19:1023–1029CrossRefGoogle Scholar
  32. 32.
    Patil MS, Patil CR, Patil SW et al (2011) Anticonvulsant activity of aqueous root extract of Ficus religiosa. J Ethnopharmacol 133(1):1–96CrossRefGoogle Scholar
  33. 33.
    Tamboli AM, Rub RA, Ghosh P et al (2012) Antiepileptic activity of lobeline isolated from the leaf of Lobelia nicotianaefolia and its effect on brain GABA level in mice. Asian Pac J Trop Biomed 2:537–542CrossRefGoogle Scholar
  34. 34.
    Agarwal NB, Agarwal NK, Mediratta PK et al (2011) Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure 20(3):257–262CrossRefGoogle Scholar
  35. 35.
    Zhu X, Shen K, Bai Y et al (2016) NADPH oxidase activation is required for pentylenetetrazole kindling-induced hippocampal autophagy. Free Radic Biol Med 94:230–242CrossRefGoogle Scholar
  36. 36.
    Khamse S, Sadr SS, Roghani M et al (2015) Rosmarinic acid exerts a neuroprotective effect in the kainate rat model of temporal lobe epilepsy: underlying mechanisms. Pharm Biol 53(12):1818–1825CrossRefGoogle Scholar
  37. 37.
    Nakano M, Ueda H, Li JY et al (2001) A potent AMPA/kainate receptor antagonist, YM90K, attenuates the loss of N-acetylaspartate in the hippocampal CA1 area after transient unilateral forebrain ischemia in gerbils. Life Sci 69(17):1–1990CrossRefGoogle Scholar
  38. 38.
    Matsumoto M, Hatakeyama T, Akai F, Brengman JM et al (1988) Prediction of stroke before and after unilateral occlusion of the common carotid artery in gerbils. Stroke 19(4):490–497CrossRefGoogle Scholar
  39. 39.
    Pan J, He H, Su Y et al (2016) GST-TAT-SOD: cell permeable bifunctional antioxidant enzyme-A potential selective radioprotector. Oxid Med Cell Longev 2016:5935080.  https://doi.org/10.1155/2016/5935080 CrossRefGoogle Scholar
  40. 40.
    Liu L, Liu Y, Cui J et al (2013) Oxidative stress induces gastric submucosal arteriolar dysfunction in the elderly. World J Gastroenterol 19(48):9439–9446CrossRefGoogle Scholar
  41. 41.
    DeGraba TJ (1998) The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. Neurology 51(Issue 3, Supplement 3):S62–S68CrossRefGoogle Scholar
  42. 42.
    Vinten-Johansen J (2004) Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 61(3):481–497CrossRefGoogle Scholar
  43. 43.
    Liu PF, Hu YC, Kang BH et al (2017) Expression levels of cleaved caspase-3 and caspase-3 in tumorigenesis and prognosis of oral tongue squamous cell carcinoma. PLoS ONE 12(7):e0180620CrossRefGoogle Scholar
  44. 44.
    Schwarzer C, Tsunashima K, Wanzenböck C et al (1997) GABAA receptor subunits in the rat hippocampus III: altered messenger RNA expression in kainic acid-induced epilepsy. Neuroscience 80(4):1019–1032CrossRefGoogle Scholar
  45. 45.
    Dam AM (2010) Epilepsy and neuron loss in the hippocampus. Epilepsia 21(6):617–629CrossRefGoogle Scholar
  46. 46.
    Cho KO, Lybrand ZR, Ito N et al (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:6606CrossRefGoogle Scholar
  47. 47.
    Scharfman HE (2007) The neurobiology of epilepsy. Curr Neurol Neurosci Rep 7(4):348–354CrossRefGoogle Scholar
  48. 48.
    Hassanzadeh P, Arbabi E, Atyabi F et al (2017) Ferulic acid exhibits antiepileptogenic effect and prevents oxidative stress and cognitive impairment in the kindling model of epilepsy. Life Sci 179:9–14CrossRefGoogle Scholar
  49. 49.
    Bo G, Yu W, Yuan-Jian Y et al (2018) Sinomenine exerts anticonvulsant profile and neuroprotective activity in pentylenetetrazole-kindled rats: involvement of inhibition of NLRP1 inflammasome. J Neuroinflammation 15(1):152CrossRefGoogle Scholar
  50. 50.
    Schmutzhard E, Pfausler B (2011) Complications of the management of status epilepticus in the intensive care unit. Epilepsia 52(Supplement s8):39–41CrossRefGoogle Scholar
  51. 51.
    Zhang G, Yu Z, Zhao H (1997) Protective effect of paeonol on repeated cerebral ischemia in rats. J Chin Med Mater 20(12):626Google Scholar

Copyright information

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

Authors and Affiliations

  • Dong-Hai Liu
    • 1
  • Elvis Agbo
    • 2
  • Shu-Hong Zhang
    • 3
  • Jin-Ling Zhu
    • 3
    Email author
  1. 1.School of Basic MedicineJiamusi UniversityJiamusiPeople’s Republic of China
  2. 2.Department of Anatomy, School of Basic MedicineJiamusi UniversityJiamusiPeople’s Republic of China
  3. 3.Department of Biology, School of Basic MedicineJiamusi UniversityJiamusiPeople’s Republic of China

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