Neuroprotective Effects of α-pinene on Memory Impairment and Apoptosis in a Pentylenetetrazol-Induced Kindling Model of Epilepsy in Rats

Hashemi, Paria; Nazarinia, Donya; Dolatshahi, Mojtaba

[Home ] [Archive]

[ فارسی ]

The Neuroscience Journal of Shefaye Khatam

Main Menu

Home

Journal Information

Articles Archive

Guide for Authors

For Reviewers

Ethical Statements

Registration

Site Facilities

Contact us

Indexed by

Search in website

Receive site information

Open Access Policy

This journal provides immediate open access to its content on the principle that making research freely available to the public supports a greater global exchange of knowledge.

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.

Articles In Press

Back to the articles list

Back to browse issues page

Neuroprotective Effects of α-pinene on Memory Impairment and Apoptosis in a Pentylenetetrazol-Induced Kindling Model of Epilepsy in Rats

Paria Hashemi

, Donya Nazarinia ^*

, Mojtaba Dolatshahi

Department of Physiology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran , e_nazarinia@yahoo.com

Abstract: (11 Views)

Introduction: Epilepsy is a chronic neurological disorder characterized by recurrent and spontaneous seizures. α-Pinene, a monoterpene found in plant essential oils, has been shown in neuroscience studies to exhibit significant biological activities, particularly anti-inflammatory and antioxidant effects. This study aimed to investigate the neuroprotective effects of α-pinene on memory impairment and neuronal apoptosis in a pentylenetetrazol (PTZ)-induced kindling model of epilepsy in rats. Materials and Methods: Male Wistar rats were randomly divided into five groups: Control, PTZ-induced kindling (intraperitoneal injection of 45 mg/kg PTZ for 10 consecutive days), PTZ + α-pinene 50 mg/kg, PTZ + α-pinene 100 mg/kg, and α-pinene 100 mg/kg. Seizure behaviors were assessed using the modified Racine scale. Short-term spatial working memory and passive avoidance memory were assessed using the Y-maze and shuttle box apparatus, respectively. Cytochrome c and caspase-3 levels were measured in hippocampal tissue using ELISA. Results: Our findings showed that PTZ-treated rats exhibited more severe seizures and pronounced memory impairment. α-Pinene, at both doses, significantly attenuated seizure intensity and duration compared with the PTZ group. Treatment with α-pinene (100 mg/kg) significantly increased latency to enter the dark chamber in the passive avoidance test and improved spontaneous alternation behavior in the Y-maze test. In addition, cytochrome c and caspase-3 levels were significantly reduced in the α-pinene (100 mg/kg) group compared with the PTZ group. Conclusion: Our findings suggest that α-pinene exerts anticonvulsant effects and improves memory performance in the PTZ-induced kindling rat model of epilepsy, potentially through modulation of apoptotic pathways, as evidenced by reduced cytochrome c and caspase-3 levels.

Keywords: Pentylenetetrazole, Seizures, Hippocampus, Caspase 3, Spatial Learning

Type of Study: Research --- Open Access, CC-BY-NC | Subject: Neurophysiology

References

1. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017; 58(4): 512-21. [DOI:10.1111/epi.13709]

2. Thome-Souza S, Kuczynski E, Assumpção Jr F, Rzezak P, Fuentes D, Fiore L, et al. Which factors may play a pivotal role on determining the type of psychiatric disorder in children and adolescents with epilepsy? Epilepsy & Behavior. 2004; 5(6): 988-94. [DOI:10.1016/j.yebeh.2004.09.001]

3. González-H G, Contreras-García IJ, Sánchez-Huerta K, Queiroz CM, Gallardo Gudiño LR, Mendoza-Torreblanca JG, et al. Levetiracetam reduced the basal excitability of the dentate gyrus without restoring impaired synaptic plasticity in rats with temporal lobe epilepsy. Brain Sciences. 2020; 10(9): 634. [DOI:10.3390/brainsci10090634]

4. Hermann BP, Struck AF, Busch RM, Reyes A, Kaestner E, McDonald CR. Neurobehavioural comorbidities of epilepsy: towards a network-based precision taxonomy. Nature Reviews Neurology. 2021; 17(12): 731-46. [DOI:10.1038/s41582-021-00555-z]

5. Tramoni-Negre E, Lambert I, Bartolomei F, Felician O. Long-term memory deficits in temporal lobe epilepsy. Revue neurologique. 2017; 173(7-8): 490-7. [DOI:10.1016/j.neurol.2017.06.011]

6. Novak A, Vizjak K, Rakusa M. Cognitive impairment in people with epilepsy. Journal of clinical medicine. 2022; 11(1): 267. [DOI:10.3390/jcm11010267]

7. Blake R, Wroe S, Breen E, McCarthy RA. Accelerated forgetting in patients with epilepsy: evidence for an impairment in memory consolidation. Brain. 2000; 123(3): 472-83. [DOI:10.1093/brain/123.3.472]

8. Butler C, Zeman A. Recent insights into the impairment of memory in epilepsy: transient epileptic amnesia, accelerated long-term forgetting and remote memory impairment. Brain. 2008; 131(9): 2243-63. [DOI:10.1093/brain/awn127]

9. Sahraei M, Rezaei F, Papi F. A Survey on the impact of metacognitive beliefs, anxiety, and depression on the stigma of epilepsy in Khoram-Abad, Iran. The Neuroscience Journal of Shefaye Khatam. 2020; 8(3): 20-8. [DOI:10.29252/shefa.8.3.20]

10. Moghadam BB, Shirian S, Karimzadeh MH, Mashaei KS. The Effect of Astaxanthin on the Treatment of Epilepsy and Brain-Spinal Cord Injury. The Neuroscience Journal of Shefaye Khatam.2025; 13(3): 101-114. [DOI:10.61882/shefa.13.3.101]

11. Khodabandeh H, Keshavarzi S, Moradian P, Edalatmanesh MA. The Effect of Hesperidin on the Cognitive-Behavioral Deficit in a Rat Model of Pentylenetetrazole-Induced Perinatal Seizures. The Neuroscience Journal of Shefaye Khatam. 2020; 8(4): 1-11. [DOI:10.29252/shefa.8.4.1]

12. Aghdash SN, Nasirifard S. The Effect of Equeous Datura Stramonium L Seed Extract on Chemical Kindling Induced by Intraperitoneal Injection of Pentylenetetrazole in Mice. The Neuroscience Journal of Shefaye Khatam.2015; 3(2): 35-40. [DOI:10.18869/acadpub.shefa.3.2.35]

13. Aghdash SN, Nasirifard S. Assessment of aqueous extract of Humulus lupulus effects on seizure induced by intraperitoneal injection of pentylenetetrazole in mice. Neurosci J Shefaye Khatam. 2015; 3: 49-54. [DOI:10.18869/acadpub.shefa.3.2.49]

14. Jeżowska-Jurczyk K, Kotas R, Jurczyk P, Nowakowska-Kotas M, Budrewicz S, Pokryszko-Dragan A. Mental disorders in patients with epilepsy. Psychiatr Pol. 2020; 54(1): 51-68. [DOI:10.12740/PP/93886]

15. Zhang X, Wu Z, Zhou X, Tao H. Mitochondrial dysfunction in epilepsy: mechanistic insights and clinical strategies. Molecular Biology Reports. 2025; 52(1): 470. [DOI:10.1007/s11033-025-10577-1]

16. Cock H. The role of mitochondria in status epilepticus. Epilepsia (Series 4). 2007; 48. [DOI:10.1111/j.1528-1167.2007.01341.x]

17. Glover HL, Schreiner A, Dewson G, Tait SW. Mitochondria and cell death. Nature cell biology. 2024; 26(9): 1434-46. [DOI:10.1038/s41556-024-01429-4]

18. Olney JW, Tenkova T, Dikranian K, Muglia LJ, Jermakowicz WJ, D'Sa C, et al. Ethanol-induced caspase-3 activation in the in vivo developing mouse brain. Neurobiology of disease. 2002; 9(2): 205-19. [DOI:10.1006/nbdi.2001.0475]

19. Chuang Y-C. Mitochondrial dysfunction and oxidative stress in seizure-induced neuronal cell death. Acta Neurol Taiwan. 2010; 19(1): 3-15.

20. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacological reviews. 2020; 72(3): 606-38. [DOI:10.1124/pr.120.019539]

21. De Bellis M, d'Orsi G, Rubino EM, Arigliano C, Carella M, Sciruicchio V, et al. Adverse effects of antiseizure medications: a review of the impact of pharmacogenetics and drugs interactions in clinical practice. Frontiers in pharmacology. 2025; 16: 1584566. [DOI:10.3389/fphar.2025.1584566]

22. 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. Molecular Neurobiology. 2023; 60(6): 3227-38. [DOI:10.1007/s12035-023-03274-2]

23. Khan‐Mohammadi‐Khorrami MK, Asle‐Rousta M, Rahnema M, Amini R. Neuroprotective effect of alpha‐pinene is mediated by suppression of the TNF‐α/NF‐κB pathway in Alzheimer's disease rat model. Journal of biochemical and molecular toxicology. 2022; 36(5): e23006. [DOI:10.1002/jbt.23006]

24. Khoshnazar M, Parvardeh S, Bigdeli MR. Alpha-pinene exerts neuroprotective effects via anti-inflammatory and anti-apoptotic mechanisms in a rat model of focal cerebral ischemia-reperfusion. Journal of Stroke and Cerebrovascular Diseases. 2020; 29(8): 104977. [DOI:10.1016/j.jstrokecerebrovasdis.2020.104977]

25. Goudarzi S, Rafieirad M. Evaluating the effect of α-pinene on motor activity, avoidance memory and lipid peroxidation in animal model of Parkinson disease in adult male rats. Research Journal of Pharmacognosy. 2017; 4(2): 53-63.

26. Saeedipour S, Rafieirad M. Anti-anxiety effect of Alpha-pinene in comparison with Diazepam in adult male rats. Feyz Medical Sciences Journal. 2020; 24(3): 253-45.

27. Hashemi P, Ahmadi S. Alpha-pinene moderates memory impairment induced by kainic acid via improving the BDNF/TrkB/CREB signaling pathway in rat hippocampus. Frontiers in Molecular Neuroscience. 2023;16:1202232. [DOI:10.3389/fnmol.2023.1202232]

28. Lüttjohann A, Fabene PF, van Luijtelaar G. A revised Racine's scale for PTZ-induced seizures in rats. Physiology & behavior. 2009; 98(5): 579-86. [DOI:10.1016/j.physbeh.2009.09.005]

29. Kraeuter A-K, Guest PC, Sarnyai Z. The Y-maze for assessment of spatial working and reference memory in mice. Pre-clinical models: Techniques and protocols: Springer; 2018. p. 105-11. [DOI:10.1007/978-1-4939-8994-2_10]

30. Taskiran AS, Ergul M. The modulator action of thiamine against pentylenetetrazole-induced seizures, apoptosis, nitric oxide, and oxidative stress in rats and SH-SY5Y neuronal cell line. Chemico-biological interactions. 2021; 340: 109447. [DOI:10.1016/j.cbi.2021.109447]

31. Guo L, Gao T, Jia X, Gao C, Tian H, Wei Y, et al. SKF83959 attenuates memory impairment and depressive-like behavior during the latent period of epilepsy via allosteric activation of the sigma-1 receptor. ACS Chemical Neuroscience. 2022; 13(22): 3198-209. [DOI:10.1021/acschemneuro.2c00629]

32. Maslarova A, Schröter S, Buchfelder M, Brandner S. FV 16 Long-term potentiation of synaptic plasticity in the temporal cortex of epilepsy patients-in search of a mechanism for memory impairment. Clinical Neurophysiology. 2022; 137: e9. [DOI:10.1016/j.clinph.2022.01.023]

33. Jung A-r, Park C-h, Choi YS, Yoo JH, Lee HW. Functional brain connectivity and memory impairment in temporal lobe epilepsy (I7. 007). Neurology. 2016; 86(16_supplement): I7. 007. [DOI:10.1212/WNL.86.16_supplement.I7.007]

34. Kaur H, Patro I, Tikoo K, Sandhir R. Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy. Neurochemistry international. 2015; 89: 40-50. [DOI:10.1016/j.neuint.2015.07.009]

35. Choudhary KM, Mishra A, Poroikov VV, Goel RK. Ameliorative effect of Curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice. European journal of pharmacology. 2013; 704(1-3): 33-40. [DOI:10.1016/j.ejphar.2013.02.012]

36. Safar MM, Shahin NN, Mohamed AF, Abdelkader NF. Suppression of BACE1 and amyloidogenic/RAGE axis by sitagliptin ameliorates PTZ kindling-induced cognitive deficits in rats. Chemico-Biological Interactions. 2020; 328: 109144. [DOI:10.1016/j.cbi.2020.109144]

37. Alachkar A, Ojha SK, Sadeq A, Adem A, Frank A, Stark H, et al. Experimental models for the discovery of novel anticonvulsant drugs: focus on pentylenetetrazole-induced seizures and associated memory deficits. Current pharmaceutical design. 2020; 26(15): 1693-711. [DOI:10.2174/1381612826666200131105324]

38. Wang L, Ding J, Zhu C, Guo B, Yang W, He W, et al. Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazole-kindled mice. International journal of molecular medicine. 2021; 48(6): 219. [DOI:10.3892/ijmm.2021.5052]

39. Pahuja M, Mehla J, Reeta K, Tripathi M, Gupta YK. Effect of Anacyclus pyrethrum on pentylenetetrazole-induced kindling, spatial memory, oxidative stress and rho-kinase II expression in mice. Neurochemical research. 2013; 38(3): 547-56. [DOI:10.1007/s11064-012-0947-2]

40. Erdoğan F, Gölgeli A, Arman F, Ersoy AÖ. The effects of pentylenetetrazole-induced status epilepticus on behavior, emotional memory, and learning in rats. Epilepsy & Behavior. 2004; 5(3): 388-93. [DOI:10.1016/j.yebeh.2004.03.001]

41. Lee G, Lee C, Park G, Jang J. Amelioration of scopolamine-induced learning and memory impairment by multiple bioactivities of traditional medicinal herbs for treatment of neurodegenerative diseases. Evid Based Complement Alternat Med Available from. 2017; 2017. [DOI:10.1155/2017/4926815]

42. Hashemi P, Moloudi MR, Rahmani H, Vahabzadeh Z, Izadpanah E. Alpha-Pinene Effect on Passive Avoidance Memory and CDK5 Gene Expression in the Rat Model of Huntington's Disease Induced by 3-Nitropropionic Acid. Scientific Journal of Kurdistan University of Medical Sciences. 2024; 29(1): 34-45. [DOI:10.61186/sjku.29.1.34]

43. Kotloski R, Lynch M, Lauersdorf S, Sutula T. Repeated brief seizures induce progressive hippocampal neuron loss and memory deficits. Progress in brain research. 2002; 135: 95-110. [DOI:10.1016/S0079-6123(02)35010-6]

44. Tobon‐Arroyave S, Villegas‐Acosta F, Ruiz‐Restrepo S, Vieco‐Duran B, Restrepo‐Misas M, Londoño‐López M. Expression of caspase‐3 and structural changes associated with apoptotic cell death of keratinocytes in oral lichen planus. Oral diseases. 2004; 10(3): 173-8. [DOI:10.1046/j.1601-0825.2003.00998.x]

45. Bascones‐Ilundain C, Gonzalez‐Moles M, Campo‐Trapero J, Gil‐Montoya J, Esparza‐Gómez G, Cano‐Sánchez J, et al. No differences in caspase‐3 and Bax expression in atrophic‐erosive vs. reticular oral lichen planus. Journal of the European Academy of Dermatology and Venereology. 2008; 22(2): 204-12. [DOI:10.1111/j.1468-3083.2007.02387.x]

46. Silva FFVE, Padín-Iruegas ME, Caponio VCA, Lorenzo-Pouso AI, Saavedra-Nieves P, Chamorro-Petronacci CM, et al. Caspase 3 and cleaved caspase 3 expression in tumorogenesis and its correlations with prognosis in head and neck cancer: a systematic review and meta-analysis. International journal of molecular sciences. 2022; 23(19): 11937. [DOI:10.3390/ijms231911937]

47. Huang J-S, Yang C-M, Wang J-S, Liou H-H, Hsieh I-C, Li G-C, et al. Caspase-3 expression in tumorigenesis and prognosis of buccal mucosa squamous cell carcinoma. Oncotarget. 2017; 8(48): 84237. [DOI:10.18632/oncotarget.20494]

Rights and permissions
	This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Back to the articles list

Back to browse issues page

Persian site map - English site map - Created in 0.17 seconds with 47 queries by YEKTAWEB 4758