Abstract
Objectives
Phytocannabinoids beyond the Δ9-tetrahy-drocannabinol have shown anticonvulsive effects. Also, alkylamides from Echinacea purpurea have been proved as cannabinomimetics. We examined the effect of the hydroalcoholic root extract of E. purpurea on pentylenetetrazol (PTZ)-induced tonic–clonic seizures and kindling model of epileptogenesis and the involvement of CB2 receptors as the mediator of this effect.
Methods
Male Wistar rats (200 ± 20 g) were used. Single intraperitoneal (i.p.) injection of PTZ (80 mg/kg) was used to induce tonic–clonic seizures. The kindling model of epileptogenesis was induced by daily injections of PTZ (37 mg/kg; i.p. for 15 days). Latency and duration of the stages were monitored for analysis. The hydroalcoholic root extract of E. purpurea was injected (i.p.) 20 min before seizure induction at the doses of 10, 50, 100 and 200 mg/kg. CB2 receptor antagonist SR144528 was injected (0.1 mg/kg; i.p.) 20 min before the Echinacea injection.
Results
In the tonic–clonic model, pretreatment with E. purpurea at the doses of 100 and 200 mg/kg significantly increased latencies to S2–S6, while it significantly decreased S6 duration and mortality rate. SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly prevented the effects of the extract on S4–S6 latencies. In the kindling model, E. purpurea at the doses of 100 and 200 mg/kg significantly delayed epileptogenesis and decreased mortality rate, while SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly blocked this effect of the extract.
Conclusions
These findings revealed the anticonvulsive and antiepileptogenesis effects of the E. purpurea root extract, which can be mediated by CB2 receptors.
Funding source: Arak University of Medical Sciences http://dx.doi.org/10.13039/501100007113
Award Identifier / Grant number: 3463
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Research funding: This study was supported by Arak University of Medical Sciences.
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Author contribution: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: There are no conflicts of interests for the authors.
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Informed consent: Not applicable.
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Ethical approval: All the experiments and animal care procedures were performed according to the Guide for the Care and Use of Laboratory Animals (8th edition; National Academies Press; 2011) and approved by the Review Board and Ethics Committee of Arak University of Medical Sciences.
References
1. Lutz, B. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem Pharmacol 2004;68:1691–8.10.1016/j.bcp.2004.07.007Search in Google Scholar PubMed
2. Di Marzo, V, Stella, N, Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 2015;16:30–42.10.1038/nrn3876Search in Google Scholar PubMed PubMed Central
3. Gil-Ordonez, A, Martin-Fontecha, M, Ortega-Gutierrez, S, Lopez-Rodriguez, ML. Monoacylglycerol lipase (MAGL) as a promising therapeutic target. Biochem Pharmacol 2018;157:18–32.10.1016/j.bcp.2018.07.036Search in Google Scholar PubMed
4. Deshpande, LS, Blair, RE, Ziobro, JM, Sombati, S, Martin, BR, DeLorenzo, RJ. Endocannabinoids block status epilepticus in cultured hippocampal neurons. Eur J Pharmacol 2007;558:52–9.10.1016/j.ejphar.2006.11.030Search in Google Scholar PubMed PubMed Central
5. Zareie, P, Sadegh, M, Moradi-Chameh, H. 2-Arachidonoylglycerol enrichment reduced epileptiform activity of the rat hippocampus induced with pentylenetetrazol. J Adv Med Biomed Res 2018;26:21–7.10.30699/jambs.26.118.21Search in Google Scholar
6. Zareie, P, Sadegh, M, Palizvan, M. Investigating the effect of enzymatic elimination of endocannabinoids inhibitors on tonic-colonic seizure provoked by PTZ. J Babol Univ Medical Sci 2016;18:49–56.Search in Google Scholar
7. de Boer, HM, Mula, M, Sander, JW. The global burden and stigma of epilepsy. Epilepsy Behav 2008;12:540–6.10.1016/j.yebeh.2007.12.019Search in Google Scholar PubMed
8. Hitiris, N, Mohanraj, R, Norrie, J, Sills, GJ, Brodie, MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res 2007;75:192–6.10.1016/j.eplepsyres.2007.06.003Search in Google Scholar PubMed
9. Hill, AJ, Williams, CM, Whalley, BJ, Stephens, GJ. Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther 2012;133:79–97.10.1016/j.pharmthera.2011.09.002Search in Google Scholar PubMed
10. Amada, N, Yamasaki, Y, Williams, CM, Whalley, BJ. Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ 2013;1:e214.10.7717/peerj.214Search in Google Scholar PubMed PubMed Central
11. dos Santos, RG, Hallak, JE, Leite, JP, Zuardi, AW, Crippa, JA. Phytocannabinoids and epilepsy. J Clin Pharm Therapeut 2015;40:135–43.10.1111/jcpt.12235Search in Google Scholar PubMed
12. Hess, EJ, Moody, KA, Geffrey, AL, Pollack, SF, Skirvin, LA, Bruno, PL, et al.. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 2016;57:1617–24.10.1111/epi.13499Search in Google Scholar PubMed
13. Gertsch, J, Pertwee, RG, Di Marzo, V. Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol 2010;160:523–9.10.1111/j.1476-5381.2010.00745.xSearch in Google Scholar PubMed PubMed Central
14. Barnes, J, Anderson, LA, Gibbons, S, Phillipson, JD. Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2005;57:929–54.10.1211/0022357056127Search in Google Scholar PubMed
15. Woelkart, K, Frye, RF, Derendorf, H, Bauer, R, Butterweck, V. Pharmacokinetics and tissue distribution of dodeca-2E,4E,8E,10E/Z-tetraenoic acid isobutylamides after oral administration in rats. Planta Med 2009;75:1306–13.10.1055/s-0029-1185631Search in Google Scholar PubMed
16. Gertsch, J, Raduner, S, Altmann, K. New natural noncannabinoid ligands for cannabinoid type-2 (CB2) receptors. J Recept Signal Transduct Res 2006;26:709–30.10.1080/10799890600942674Search in Google Scholar PubMed
17. Woelkart, K, Bauer, R. The role of alkamides as an active principle of echinacea. Planta Med 2007;73:615–23.10.1055/s-2007-981531Search in Google Scholar PubMed
18. Velíšková, J. Behavioral characterization of seizures in rats. In: Models of seizures and epilepsy. Elsevier; 2006:601–11 pp.10.1016/B978-012088554-1/50050-5Search in Google Scholar
19. Eraković, V, Župan, G, Varljen, J, Laginja, J, Simonić, A. Altered activities of rat brain metabolic enzymes caused by pentylenetetrazol kindling and pentylenetetrazol—induced seizures. Epilepsy Res 2001;43:165–73.10.1016/S0920-1211(00)00197-2Search in Google Scholar
20. Woelkart, K, Xu, W, Pei, Y, Makriyannis, A, Picone, RP, Bauer, R. The endocannabinoid system as a target for alkamides from Echinacea angustifolia roots. Planta Med 2005;71:701–5.10.1055/s-2005-871290Search in Google Scholar PubMed
21. Lippiello, P, Balestrini, S, Leo, A, Coppola, A, Citraro, R, Elia, M, et al.. From cannabis to cannabidiol to treat epilepsy, where are we? Curr Pharmaceut Des 2016;22:6426–33.10.2174/1381612822666160831122722Search in Google Scholar PubMed
22. Karanian, DA, Karim, SL, Wood, JT, Williams, JS, Lin, S, Makriyannis, A, et al.. Endocannabinoid enhancement protects against kainic acid-induced seizures and associated brain damage. J Pharmacol Exp Therapeut 2007;322:1059–66.10.1124/jpet.107.120147Search in Google Scholar PubMed
23. Zareie, P, Sadegh, M, Palizvan, MR, Moradi-Chameh, H. Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic-clonic seizures. Metab Brain Dis 2018;33:939–48.10.1007/s11011-018-0195-5Search in Google Scholar PubMed
24. Raduner, S, Majewska, A, Chen, J-Z, Xie, X-Q, Hamon, J, Faller, B, et al.. Alkylamides from Echinacea are a new class of cannabinomimetics cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J Biol Chem 2006;281:14192–206.10.1074/jbc.M601074200Search in Google Scholar PubMed
25. Chicca, A, Raduner, S, Pellati, F, Strompen, T, Altmann, KH, Schoop, R, et al.. Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts. Int Immunopharm 2009;9:850–8.10.1016/j.intimp.2009.03.006Search in Google Scholar PubMed
26. Gertsch, J, Schoop, R, Kuenzle, U, Suter, A. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Lett 2004;577:563–9.10.1016/j.febslet.2004.10.064Search in Google Scholar PubMed
27. Hinz, B, Woelkart, K, Bauer, R. Alkamides from Echinacea inhibit cyclooxygenase-2 activity in human neuroglioma cells. Biochem Biophys Res Commun 2007;360:441–6.10.1016/j.bbrc.2007.06.073Search in Google Scholar PubMed
28. Temp, FR, Marafiga, JR, Milanesi, LH, Duarte, T, Rambo, LM, Pillat, MM, et al.. Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice. Eur J Pharmacol 2017;810:15–25.10.1016/j.ejphar.2017.05.013Search in Google Scholar PubMed
29. Hajos, N, Holderith, N, Nemeth, B, Papp, OI, Szabo, GG, Zemankovics, R, et al.. The effects of an Echinacea preparation on synaptic transmission and the firing properties of CA1 pyramidal cells in the hippocampus. Phytother Res 2012;26:354–62.10.1002/ptr.3556Search in Google Scholar PubMed
30. Haller, J, Hohmann, J, Freund, TF. The effect of Echinacea preparations in three laboratory tests of anxiety: comparison with chlordiazepoxide. Phytother Res 2010;24:1605–13.10.1002/ptr.3181Search in Google Scholar PubMed
31. Navidhamidi, M, Ghasemi, M, Mehranfard, N. Epilepsy-associated alterations in hippocampal excitability. Rev Neurosci 2017;28:307–34.10.1515/revneuro-2016-0059Search in Google Scholar PubMed
© 2021 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
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- A preliminary systematic review and meta-analysis on the effects of heart rate variability biofeedback on heart rate variability and respiration of athletes
- The potential positive epigenetic effects of various mind-body therapies (MBTs): a narrative review
- The effect of Chlorella vulgaris on obesity related metabolic disorders: a systematic review of randomized controlled trials
- Biological and medicinal application of Cucumis sativus Linn. – review of current status with future possibilities
- The effect of the herbal medicine on severity of cyclic mastalgia: a systematic review and meta-analysis
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- Chemical compositions, antibacterial, antifungal and cytotoxic effects of Alhagi mannifera five extracts
- Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor
- Fermented maize slurry (Ogi) and its supernatant (Omidun) mitigate elevated intraocular pressure by modulating BDNF expression and glial plasticity in the retina-gut axis of glaucomatous rats
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- Antibiofilm action of Persea americana glycolic extract over Acinetobacter baumannii and absence of toxicity in Galleria mellonella
- Validation of Unani concept of Abadāl-i-Adwiya (drug substitution) by physicochemical standardization and hepatoprotective activity of Aristolochia rotunda Linn. and its substitute Curcuma Zedoaria Rosc. in albino Wistar rats
- Cinnamon oil as a co-chemotherapy agent through inhibition of cell migration and MMP-9 expression on 4T1 cells
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- Quantification of anacardic acid, the toxic component in raw and purified samples of Semecarpus anacardium L. by Siddha purification processes
- Molecular docking and molecular dynamics approach to identify potential compounds in Huperzia squarrosa for treating Alzheimer’s disease
- Evaluation of ethanol extracts from three species of Artocarpus as natural gastroprotective agents: in vivo and histopathological studies
- Attenuation of cisplatin induced myelosuppression by methanol extract of Cedrus deodara in Wistar rats
- Acute and sub-acute toxicity assessment of the standardized extract of Sanguisorba minor in vivo
- Efficacy of lettuce seed syrup on insomnia in patients with breast cancer: a pilot double blind randomized placebo controlled clinical trial
- The effect of aromatherapy with rose essential oil on apparent anxiety in patients with myocardial infarction
- Effect of Jyoti-Trataka on intraocular pressure, autonomic control, and blood glucose in diabetic patients with high-tension primary open-angle glaucoma: a randomized-controlled trial
- Efficacy of Ḥammām-i-yābis (dry bath) in metabolic syndrome: a single arm, open-labelled clinical trial
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Articles in the same Issue
- Frontmatter
- Reviews
- A preliminary systematic review and meta-analysis on the effects of heart rate variability biofeedback on heart rate variability and respiration of athletes
- The potential positive epigenetic effects of various mind-body therapies (MBTs): a narrative review
- The effect of Chlorella vulgaris on obesity related metabolic disorders: a systematic review of randomized controlled trials
- Biological and medicinal application of Cucumis sativus Linn. – review of current status with future possibilities
- The effect of the herbal medicine on severity of cyclic mastalgia: a systematic review and meta-analysis
- Research Articles
- Chemical compositions, antibacterial, antifungal and cytotoxic effects of Alhagi mannifera five extracts
- Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor
- Fermented maize slurry (Ogi) and its supernatant (Omidun) mitigate elevated intraocular pressure by modulating BDNF expression and glial plasticity in the retina-gut axis of glaucomatous rats
- Levetiracetam exposure during prenatal and postnatal period induces cognitive decline in rat offsprings, not completely prevented by Bacopa monnieri
- Antibiofilm action of Persea americana glycolic extract over Acinetobacter baumannii and absence of toxicity in Galleria mellonella
- Validation of Unani concept of Abadāl-i-Adwiya (drug substitution) by physicochemical standardization and hepatoprotective activity of Aristolochia rotunda Linn. and its substitute Curcuma Zedoaria Rosc. in albino Wistar rats
- Cinnamon oil as a co-chemotherapy agent through inhibition of cell migration and MMP-9 expression on 4T1 cells
- Assessment of biochemical changes in normal and diabetic rats treated by phenolic enriched extracts of Juglans regia L. barks
- Influence of Clerodendrum volubile leaf extract on doxorubicin-induced toxicity and inhibition of carbonyl reductase mediated metabolism
- Quantification of anacardic acid, the toxic component in raw and purified samples of Semecarpus anacardium L. by Siddha purification processes
- Molecular docking and molecular dynamics approach to identify potential compounds in Huperzia squarrosa for treating Alzheimer’s disease
- Evaluation of ethanol extracts from three species of Artocarpus as natural gastroprotective agents: in vivo and histopathological studies
- Attenuation of cisplatin induced myelosuppression by methanol extract of Cedrus deodara in Wistar rats
- Acute and sub-acute toxicity assessment of the standardized extract of Sanguisorba minor in vivo
- Efficacy of lettuce seed syrup on insomnia in patients with breast cancer: a pilot double blind randomized placebo controlled clinical trial
- The effect of aromatherapy with rose essential oil on apparent anxiety in patients with myocardial infarction
- Effect of Jyoti-Trataka on intraocular pressure, autonomic control, and blood glucose in diabetic patients with high-tension primary open-angle glaucoma: a randomized-controlled trial
- Efficacy of Ḥammām-i-yābis (dry bath) in metabolic syndrome: a single arm, open-labelled clinical trial
- Effect of Ḥijāma (wet cupping), Dalk (massage) and Bukhūr (medicated steam) in amelioration of Waja al-Zahr (non-specific low back pain) – an open prospective clinical trial
- Effect of yoga on cardiovascular functions and psychological aspects of people on public service-related work: an exploratory study