Skip to main content

Advertisement

SpringerLink
Log in

Alpha-Pinene Exerts Antiseizure Effects by Preventing Oxidative Stress and Apoptosis in the Hippocampus in a Rat Model of Temporal Lobe Epilepsy Induced by Kainate

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Oxidative stress and apoptosis following seizures play pivotal roles in the consequences of repeated seizures. Beneficial effects of alpha-pinene (APN) have been reported in some experimental models of neurodegenerative diseases. However, its neuroprotective efficacy in a rat model of temporal lobe epilepsy (TLE) induced by kainic acid (KA) has remained unexplored. We aimed to explore the possible antiseizure effects of APN pretreatment and underlying molecular mechanisms in a rat model of TLE induced by KA. TLE was induced in male Wistar rats by intracerebroventricular injection of KA. APN at a dose of 50 mg/kg/day was intraperitoneally injected for 2 weeks before induction of TLE. One day after the induction of TLE, behavioral expressions of seizure were recorded and scored using Racine’s scale. Furthermore, the hippocampal levels of oxidative stress markers, B-cell lymphoma 2 (Bcl2), BCL2-associated X protein (BAX), and c-Jun N-terminal kinase (JNK) protein levels were also assessed. Histopathological assessment in the hippocampus was performed with Nissl staining 5 days following induction of TLE. The results revealed that APN pretreatment alleviated epileptic seizures, diminished oxidative stress indicators, blocked the mitochondrial apoptotic pathway via decreasing BAX and raising BCL2 protein levels in the hippocampus at least partly through inhibiting JNK activity, and decreased neuronal death in the CA3 and hilus regions. These findings reveal that APN pretreatment mitigates KA-induced seizures by blocking oxidative stress and neuronal damage factors. It can be concluded that APN has a potent potential to be considered an antiseizure medication, but it needs further investigation.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The datasets of the current study are available from the corresponding author upon reasonable request.

References

  1. Engel J Jr (1996) Introduction to temporal lobe epilepsy. Epilepsy Res. 26:141–50. https://doi.org/10.1016/s0920-1211(96)00043-5

    Article  PubMed  Google Scholar 

  2. Malmgren K, Thom M (2012) Hippocampal sclerosis–origins and imaging. Epilepsia. 53(Suppl 4):19–33. https://doi.org/10.1111/j.1528-1167.2012.03610.x

    Article  CAS  PubMed  Google Scholar 

  3. Téllez-Zenteno JF, Hernández-Ronquillo L (2012) A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res Treat. 2012:630853. https://doi.org/10.1155/2012/630853

    Article  PubMed  Google Scholar 

  4. Gourmaud S, Shou H, Irwin DJ, Sansalone K, Jacobs LM, Lucas TH et al (2020) Alzheimer-like amyloid and tau alterations associated with cognitive deficit in temporal lobe epilepsy. Brain. 143:191–209. https://doi.org/10.1093/brain/awz381

    Article  PubMed  Google Scholar 

  5. Jefferys J, Steinhäuser C, Bedner P (2016) Chemically-induced TLE models: topical application. J Neurosci Methods. 260:53–61. https://doi.org/10.1016/j.jneumeth.2015.04.011

    Article  CAS  PubMed  Google Scholar 

  6. Nirwan N, Vyas P, Vohora D (2018) Animal models of status epilepticus and temporal lobe epilepsy: a narrative review. Rev Neurosci. 29:757–70. https://doi.org/10.1515/revneuro-2017-0086

    Article  PubMed  Google Scholar 

  7. Lévesque M, Avoli M (2013) The kainic acid model of temporal lobe epilepsy. Neurosci Biobehav Rev. 37:2887–99. https://doi.org/10.1016/j.neubiorev.2013.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Henshall DC, Simon RP (2005) Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab. 25:1557–72. https://doi.org/10.1038/sj.jcbfm.9600149

    Article  CAS  PubMed  Google Scholar 

  9. Anilkumar U, Prehn JH (2014) Anti-apoptotic BCL-2 family proteins in acute neural injury. Front Cell Neurosci. 8:281. https://doi.org/10.3389/fncel.2014.00281

    Article  PubMed  PubMed Central  Google Scholar 

  10. Henshall DC, Engel T (2013) Contribution of apoptosis-associated signaling pathways to epileptogenesis: lessons from Bcl-2 family knockouts. Front Cell Neurosci. 7:110. https://doi.org/10.3389/fncel.2013.00110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Henshall DC, Meldrum BS (2012) Cell death and survival mechanisms after single and repeated brief seizures. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s Basic Mechanisms of the Epilepsies. National Center for Biotechnology Information (US), Bethesda

    Google Scholar 

  12. Kilany A, Raouf ER, Gaber AA, Aloush TK, Aref HA, Anwar M et al (2012) Elevated serum Bcl-2 in children with temporal lobe epilepsy. Seizure. 21:250–3. https://doi.org/10.1016/j.seizure.2012.01.004

    Article  PubMed  Google Scholar 

  13. Xu S, Pang Q, Liu Y, Shang W, Zhai G, Ge M (2007) Neuronal apoptosis in the resected sclerotic hippocampus in patients with mesial temporal lobe epilepsy. J Clin Neurosci. 14:835–40. https://doi.org/10.1016/j.jocn.2006.08.002

    Article  PubMed  Google Scholar 

  14. Auladell C, de Lemos L, Verdaguer E, Ettcheto M, Busquets O, Lazarowski A et al (2017) Role of JNK isoforms in the kainic acid experimental model of epilepsy and neurodegeneration. Front Biosci (Landmark Ed). 22:795–814. https://doi.org/10.2741/4517

    Article  CAS  PubMed  Google Scholar 

  15. Yarza R, Vela S, Solas M, Ramirez MJ (2015) c-Jun N-terminal Kinase (JNK) Signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol. 6:321. https://doi.org/10.3389/fphar.2015.00321

    Article  CAS  PubMed  Google Scholar 

  16. Busquets O, Ettcheto M, Cano A, R Manzine P, Sánchez-Lopez E, Espinosa-Jiménez T et al (2019) Role of c-Jun N-terminal kinases (JNKs) in epilepsy and metabolic cognitive impairment. Int J Mol Sci. 21:255. https://doi.org/10.3390/ijms21010255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zou J, Yi S, Niu L, Zhou H, Lin Z, Wang Y et al (2021) Neuroprotective effect of ultrasound neuromodulation on kainic acid- induced epilepsy in mice. IEEE Trans Ultrason Ferroelectr Freq Control. 68:3006–16. https://doi.org/10.1109/tuffc.2021.3079628

    Article  PubMed  Google Scholar 

  18. Puttachary S, Sharma S, Stark S, Thippeswamy T (2015) Seizure-induced oxidative stress in temporal lobe epilepsy. Biomed Res Int. 2015:745613. https://doi.org/10.1155/2015/745613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Folbergrová J, Kunz WS (2012) Mitochondrial dysfunction in epilepsy. Mitochondrion. 12:35–40. https://doi.org/10.1016/j.mito.2011.04.004

    Article  CAS  PubMed  Google Scholar 

  20. Tashakori-Miyanroudi M, Ramazi S, Hashemi P, Nazari-Serenjeh M, Baluchnejadmojarad T, Roghani M (2022) Acetyl-L-carnitine exerts neuroprotective and anticonvulsant effect in kainate murine model of temporal lobe epilepsy. J Mol Neurosci. 72:1224–33. https://doi.org/10.1007/s12031-022-01999-8

    Article  CAS  PubMed  Google Scholar 

  21. Lasoń W, Leśkiewicz M (2013) Effect of plant polyphenols on seizures–animal studies. J Epileptol. 21:79–87. https://doi.org/10.21307/joepi-2015-0007

    Article  Google Scholar 

  22. Shin EJ, Jeong JH, Chung YH, Kim WK, Ko KH, Bach JH et al (2011) Role of oxidative stress in epileptic seizures. Neurochem Int. 59:122–37. https://doi.org/10.1016/j.neuint.2011.03.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Allenspach M, Steuer C (2021) α-Pinene: a never-ending story. Phytochemistry. 190:112857. https://doi.org/10.1016/j.phytochem.2021.112857

    Article  CAS  PubMed  Google Scholar 

  24. Khoshnazar M, Bigdeli MR, Parvardeh S, Pouriran R (2019) Attenuating effect of α-pinene on neurobehavioural deficit, oxidative damage and inflammatory response following focal ischaemic stroke in rat. J Pharm Pharmacol. 71:1725–33. https://doi.org/10.1111/jphp.13164

    Article  CAS  PubMed  Google Scholar 

  25. Chen W, Liu Y, Li M, Mao J, Zhang L, Huang R et al (2015) Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. J Pharmacol Sci. 127:332–8. https://doi.org/10.1016/j.jphs.2015.01.008

    Article  CAS  PubMed  Google Scholar 

  26. Khoshnazar M, Parvardeh S, Bigdeli MR (2020) Alpha-pinene exerts neuroprotective effects via anti-inflammatory and anti-apoptotic mechanisms in a rat model of focal cerebral ischemia-reperfusion. J Stroke Cerebrovasc Dis. 29:104977. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104977

    Article  PubMed  Google Scholar 

  27. Zamyad M, Abbasnejad M, Esmaeili-Mahani S, Mostafavi A, Sheibani V (2019) The anticonvulsant effects of Ducrosia anethifolia (Boiss) essential oil are produced by its main component alpha-pinene in rats. Arq Neuropsiquiatr. 77:106–14. https://doi.org/10.1590/0004-282x20180147

    Article  PubMed  Google Scholar 

  28. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, San Diego

    Google Scholar 

  29. Saghaei M (2004) Random allocation software for parallel group randomized trials. BMC Med Res Methodol. 4:26. https://doi.org/10.1186/1471-2288-4-26

    Article  PubMed  PubMed Central  Google Scholar 

  30. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. ElectroencephalogrClin Neurophysiol. 32:281–94. https://doi.org/10.1016/0013-4694(72)90177-0

    Article  CAS  Google Scholar 

  31. Vazifehkhah S, Ali MK, Babae JF, Hashemi P, Alireza MS, Nikbakht F (2020) Evaluation of the ameliorative effects of oral administration of metformin on epileptogenesis in the temporal lobe epilepsy model in rats. Life Sci. 257:118066. https://doi.org/10.1016/j.lfs.2020.118066

    Article  CAS  PubMed  Google Scholar 

  32. Kandratavicius L, Balista PA, Lopes-Aguiar C, Ruggiero RN, Umeoka EH, Garcia-Cairasco N et al (2014) Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. 10:1693–705. https://doi.org/10.2147/ndt.S50371

    Article  PubMed  PubMed Central  Google Scholar 

  33. Rusina E, Bernard C, Williamson A. The kainic acid models of temporal lobe epilepsy. eNeuro. 2021;8. https://doi.org/10.1523/eneuro.0337-20.2021.

  34. Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K et al (2020) Alpha-pinene and dizocilpine (MK-801) attenuate kindling development and astrocytosis in an experimental mouse model of epilepsy. IBRO Rep. 9:102–14. https://doi.org/10.1016/j.ibror.2020.07.007

    Article  PubMed  PubMed Central  Google Scholar 

  35. Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, Rodríguez-Martínez E, Gómez PY (2014) Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid Med Cell Longev. 2014:293689. https://doi.org/10.1155/2014/293689

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zaja-Milatovic S, Gupta RC, Aschner M, Montine TJ, Milatovic D (2008) Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum. Neurotoxicology. 29:621–7. https://doi.org/10.1016/j.neuro.2008.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baluchnejadmojarad T, Roghani M (2013) Coenzyme q10 ameliorates neurodegeneration, mossy fiber sprouting, and oxidative stress in intrahippocampal kainate model of temporal lobe epilepsy in rat. J Mol Neurosci. 49:194–201. https://doi.org/10.1007/s12031-012-9886-2

    Article  CAS  PubMed  Google Scholar 

  38. Kwon JY, Jeon MT, Jung UJ, Kim DW, Moon GJ, Kim SR (2019) Perspective: therapeutic potential of flavonoids as alternative medicines in epilepsy. Adv Nutr. 10:778–90. https://doi.org/10.1093/advances/nmz047

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sarlo GL, Holton KF (2021) Brain concentrations of glutamate and GABA in human epilepsy: a review. Seizure. 91:213–27. https://doi.org/10.1016/j.seizure.2021.06.028

    Article  PubMed  Google Scholar 

  40. Kratzer S, Irl H, Mattusch C, Bürge M, Kurz J, Kochs E et al (2014) Tranexamic acid impairs γ-aminobutyric acid receptor type A-mediated synaptic transmission in the murine amygdala: a potential mechanism for drug-induced seizures? Anesthesiology. 120:639–49. https://doi.org/10.1097/aln.0000000000000103

    Article  CAS  PubMed  Google Scholar 

  41. Sandhu MRS, Gruenbaum BF, Gruenbaum SE, Dhaher R, Deshpande K, Funaro MC et al (2021) Astroglial glutamine synthetase and the pathogenesis of mesial temporal lobe epilepsy. Front Neurol. 12:665334. https://doi.org/10.3389/fneur.2021.665334

    Article  PubMed  PubMed Central  Google Scholar 

  42. Diniz TC, Silva JC, Lima-Saraiva SRGd, Ribeiro FPRdA, Pacheco AGM, de Freitas RM et al (2015) The role of flavonoids on oxidative stress in epilepsy. Oxid Med Cell Longev. 2015:171756

    Article  PubMed  PubMed Central  Google Scholar 

  43. Woo J, Lee CJ (2020) Sleep-enhancing effects of phytoncide via behavioral, electrophysiological, and molecular modeling approaches. Exp Neurobiol. 29:120–9. https://doi.org/10.5607/en20013

    Article  PubMed  PubMed Central  Google Scholar 

  44. Weston-Green K, Clunas H, Jimenez Naranjo C (2021) A review of the potential use of pinene and linalool as terpene-based medicines for brain health: discovering novel therapeutics in the flavours and fragrances of cannabis. Front Psychiatry. 12:583211. https://doi.org/10.3389/fpsyt.2021.583211

    Article  PubMed  PubMed Central  Google Scholar 

  45. Waldbaum S, Patel M (2010) Mitochondria, oxidative stress, and temporal lobe epilepsy. Epilepsy Res. 88:23–45

    Article  CAS  PubMed  Google Scholar 

  46. Devi PU, Manocha A, Vohora D (2008) Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers. Expert Opin Pharmacother. 9:3169–77

    Article  CAS  PubMed  Google Scholar 

  47. Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, Rodríguez-Martínez E, Yescas Gómez P (2014) Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid Med Cell Longev. 2014:293689

    Article  PubMed  PubMed Central  Google Scholar 

  48. Shin E-J, Jeong JH, Chung YH, Kim W-K, Ko K-H, Bach J-H et al (2011) Role of oxidative stress in epileptic seizures. Neurochem Int. 59:122–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang CC, Ho YH, Hung CF, Kuo JR, Wang SJ (2020) Xanthohumol, an active constituent from hope, affords protection against kainic acid-induced excitotoxicity in rats. Neurochem Int. 133:104629. https://doi.org/10.1016/j.neuint.2019.104629

    Article  CAS  PubMed  Google Scholar 

  50. Wang L, Song LF, Chen XY, Ma YL, Suo JF, Shi JH et al (2019) MiR-181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther. 25:112–22. https://doi.org/10.1111/cns.12991

    Article  CAS  PubMed  Google Scholar 

  51. Rufino AT, Ribeiro M, Judas F, Salgueiro L, Lopes MC, Cavaleiro C et al (2014) Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity. J Nat Prod. 77:264–9. https://doi.org/10.1021/np400828x

    Article  CAS  PubMed  Google Scholar 

  52. Karthikeyan R, Kanimozhi G, Prasad NR, Agilan B, Ganesan M, Srithar G (2018) Alpha pinene modulates UVA-induced oxidative stress, DNA damage and apoptosis in human skin epidermal keratinocytes. Life Sci. 212:150–8. https://doi.org/10.1016/j.lfs.2018.10.004

    Article  CAS  PubMed  Google Scholar 

  53. Kitamura Y, Ota T, Matsuoka Y, Okazaki M, Kakimura J, Tooyama I et al (1998) Kainic acid-induced neuronal loss and glial changes in the hippocampal CA3 of p53-deficient mouse. Neurosci Lett. 255:57–60. https://doi.org/10.1016/s0304-3940(98)00714-9

    Article  CAS  PubMed  Google Scholar 

  54. Meng DW, Liu HG, Yang AC, Zhang K, Zhang JG (2016) Stimulation of anterior thalamic nuclei protects against seizures and neuronal apoptosis in hippocampal CA3 region of kainic acid-induced epileptic rats. Chin Med J (Engl). 129:960–6. https://doi.org/10.4103/0366-6999.179799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Khan-Mohammadi-Khorrami M-K, Asle-Rousta M, Rahnema M, Amini R (2020) The effect of alpha-pinene on amyloid-beta-induced neuronal death and depression in male Wistar rats. J Ardabil Univ Med Sci. 20:456–64. https://doi.org/10.52547/jarums.20.4.456

    Article  Google Scholar 

  56. Aydin E, Türkez H, Geyikoğlu F (2013) Antioxidative, anticancer and genotoxic properties of α-pinene on N2a neuroblastoma cells. Biologia. 68:1004–9. https://doi.org/10.2478/s11756-013-0230-2

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by the office of the Vice President for Research and Technology, University of Kurdistan (Grant No. 1399).

Author information

Authors and Affiliations

  1. Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran

    Paria Hashemi & Shamseddin Ahmadi

Authors
  1. Paria Hashemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shamseddin Ahmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Paria Hashemi: conceptualization and design of the work, acquisition, analysis, and interpretation of data, and writing — original draft preparation. Shamseddin Ahmadi: conceptualization and design of the work, supervision, project administration, funding, and writing — reviewing and editing.

Corresponding author

Correspondence to Shamseddin Ahmadi.

Ethics declarations

Ethics Approval

All procedures were done according to the Guide for the Care and Use of Laboratory Animals (2011) prepared by the National Academy of Sciences’ Institute for Laboratory Animal Research. The Research Ethics Committee (REC) at the University of Kurdistan approved the study protocol (IR.UOK.REC.1400.024).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashemi, P., Ahmadi, S. Alpha-Pinene Exerts Antiseizure Effects by Preventing Oxidative Stress and Apoptosis in the Hippocampus in a Rat Model of Temporal Lobe Epilepsy Induced by Kainate. Mol Neurobiol 60, 3227–3238 (2023). https://doi.org/10.1007/s12035-023-03274-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03274-2

Keywords

Search

Navigation