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Farelerde pentilentetrazol ile oluşturulan epilepsiye endokannabinoidlerin etkisi

Year 2020, Volume: 4 Issue: 3, 209 - 215, 29.10.2020
https://doi.org/10.30565/medalanya.690410

Abstract

Amaç: Pentilentetrazol (PTZ) yaygın antikonvülzan olduğu varsayılan ilaçların değerlendirilmesi için kullanılan bir maddedir ve sinir liflerinin tekrarlayan şekilde uyarılmasını ve refrakter süresinin kısaltılmasını sağlar. Anandamid, nöronlarda sentezlenen ve depolarizasyon sırasında atılan bir endokannabinoiddir ve çok hızlı bir şekilde inaktive olur. Epilepsi gibi sinirsel bozukluklarda, yüksek anandamid düzeyleri gözlenmiştir. Etanol akut bir uygulama sonrası, antikonvülsif etkisi olan bir psikoaktif maddedir, ancak yüksek dozlarda tekrar tekrar verilmesi prokonvülsan etkiye yol açar. Bu çalışmada amacımız endokannabinoidlerin farelerde PTZ kaynaklı epileptik nöbetleri indükleyen anandamidin etkisini, kannabinoid reseptörlerinin tiplerini belirleyerek araştırmaktı.

Yöntemler: Küçük hayvan deney modelimizde, 25-35 gr ağırlığında otuz iki İsviçre albino erkek fare kullanıldı. Çalışma sırasında, deney hayvanları; kontrol, anandamid, anandamidin sentetik analoğu (WIN 55.212-2) ve etanol olarak rastgele dört gruba ayrıldı. Epileptik atakların sayısı, ilk epileptik atak süresi, epileptik atakların toplam süresi ve PTZ enjeksiyonundan sonraki ilk ataktaki bekleme, mortalite ve alevlenme gelişim süresi her grupla karşılaştırıldı.


Bulgular:
WIN 55.212-2, anandamid ve etanol gruplarının tümünde mortalite oranı ve nöbet süresi anlamlı olarak daha düşüktü. PTZ enjeksiyonu öncesi etanol ve anandamid uygulandığında gecikme süreleri anlamlı olarak yüksek bulundu; ancak gruplar arasında bir fark yoktu. Bununla birlikte, benzer bir ilişki WIN 55.212-2 ve etanol arasında da mevcut değildi.

Sonuç: Endokannabinoid anandamid’in gözlenen antiepileptik etkisinin, çözücüsü olan etanol’ün etkisine bağlı olduğu söylenebilir; fakat bu etki de analoğu olan WIN 55.212-2 ile gözlenmemiştir. Her iki endokannabinoid de kannabinoid reseptörlerini etkilese de, bunların etkileri arasındaki söz konusu fark, onların farklı farmakokinetik, metabolizma ya da yıkım ürünlerine veya aktif metabolitlerine de bağlı olabilir.

References

  • 1. German SP, Aıda SV, German SM. Effect of extracellular long-time microperfusion of high concentrations of glutamate and glycine on picrotoxin seizure thresholds in the hippocampus of freely moving rats. Brain Res. 2000; 888: 19-25. PMID:11146048 DOI:10.1016/s0006-8993(00)02974-7
  • 2. Rocha L, Brıones M, Ackermann RF. Pentylenetetrazole-induced kindling:early involvement of excitatory and inhibitory systems. Epilepsy Res. 1996; 26: 105-113. PMID:8985692 DOI:10.1016/s0920-1211(96)00046-0
  • 3. Urushıtanı M, Nakamızo T, Inoue R. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. J Neurosci Res. 2001; 63: 377-387. PMID:11223912 DOI:10.1002/1097-4547
  • 4. Prast H, Phılıppu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2000; 64: 51-68. PMID:11250062 DOI:10.1016/s0301-0082(00)00044-7
  • 5. Osonoe K, Morı N, Suzukı K. Antiepileptic effects of inhibitors of nitric oxide synthase examined in pentylene-tetrazole-induced seizures in rats. Brain Res. 1994; 663: 338-340. PMID:7533045 DOI:10.1016/0006-8993(94)91283-1
  • 6. Devane W.A, Hanus L, Breuer A, Pertwe R.G, Stevenson L.A, Gerlin G, Gibson D, Mandembaum A, Ettinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to cannabinoid receptor. Science. 1992; 258: 1946-1949. PMID:1470919 DOI:10.1126/science.1470919
  • 7. Hanus L, Gopher A, Almog S, Mechoulam R. Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J. Med. Chem. 1993; 36: 3032-3034. PMID:8411021 DOI:10.1021/jm00072a026
  • 8. Felder C.C, Nielsen A, Briley E.M, Palkovits M, Priller J, Axelrod J, Nuguyen D.N, Richardson J.M, Riggin R.M, Coppel G.A, Paul S.M, Becker G.W. Isolation and measurement of the endogenous canabinoid receptor antagonist in the brain and peripheral tissues of human and rat. FEBS. Lett. 1996; 393: 231-5. PMID:8814296 DOI:10.1016/0014-5793(96)00891-5
  • 9. Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur. J. Pharmacol. 1998; 359: 1-18. PMID: 9831287 DOI: 10.1016/s0014-2999(98)00649-9
  • 10. Felder C. C, Briley E. M, Axelrod J. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 7656-7660. PMID:8395053PMCID:PMC47201 DOI:10.1073/pnas.90.16.7656
  • 11. Mackıe K, Devane W. A, Hılle B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol. Pharmacol. 1993; 44: 498-503. PMID:8371711
  • 12. Pertwee R. G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997; 4: 129-180. PMID:9336020 DOI:10.1016/s0163-7258(97)82001-3
  • 13. Hansen H. S, Moesgaard B, Hansen H. H, Schousboe A, Petersen G. Formation of N-acyl-phosphatidylethanolamine and N-acyl-etholamine (including anandamide) during glutamate-induced neurotoxicity. Lipids. 1999; 34: 327-330. PMID:10419193 DOI:10.1007/bf02562333
  • 14. Hansen H. H. Anandamide, but not 2-arachidonylglycerol, accumulates during in vivo neurodegeneration. J Neurochem. 2001; 78: 1415-1427. PMID:11579150 DOI:10.1046/j.1471-4159.2001.00542.x
  • 15. Sinor A. D, Irvin S. M, Greenberg D. A. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett. 2000; 278: 157-160. PMID:10653017 DOI:10.1016/s0304-3940(99)00922-2
  • 16. Nagayama T, Sinor A. D, Simon R. P, Chen J, Graham S. H, Jin K, Greenberg D. A. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999; 19: 2987-2995. PMID:10191316 PMCID:PMC6782289
  • 17. Mechoulam R. Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):93-9. PMID:12052029 DOI:10.1054/plef.2001.0340
  • 18. Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998; 21: 521-528. PMID:9881850 DOI:10.1016/s0166-2236(98)01283-1
  • 19. Piomelli D, Beltramo M, Glasnapp S. Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci USA. 1999; 96: 5802-5807. PMID:10318965 PMCID:PMC21941 DOI:10.1073/pnas.96.10.5802
  • 20. Di Marzo V. Biosynthesis and inactivation of endocannabinoids:relevance to their proposed role as neuromodulators. Life Sci. 1999; 65: 645-655. PMID:10462065 DOI:10.1016/s0024-3205(99)00287-8
  • 21. Hillard C. J, Jarrahian A. The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids. 2000; 108: 123-124 PMID:11106786 DOI:10.1016/s0009-3084(00)00191-2
  • 22. Maccarrone M, Van Der Stelt M, Rossi A, Veldink G. A, Vliegenthart J. F. G, Finazzi Agro A. Anandamide hydrolysis by human cells in culture and brain. J Biol Chem. 1998; 273: 32332-32339. PMID:9822713 DOI:10.1074/jbc.273.48.32332
  • 23. Ueda N, Puffenbarger R. A, Yamamoto S. Deutsch D. G. The fatty acid amide hydrolase (FAAH). Chem Phys. 2000; 108: 107-121. PMID:11106785 DOI:10.1016/s0009-3084(00)00190-0
  • 24. Steffens M, Schulze-Bonhage A, Surges R, Feuerstein TJ. Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids. Neurosci Lett. 2005 Sep 2;385(1):13-7. PMID: 15923084 DOI: 10.1016/j.neulet.2005.05.019
  • 25. Steffens M, Schulze-Bonhage A, Surges R, Feuerstein TJ. Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids.Neurosci Lett. 2005 May. PMID:15923084 DOI:10.1016/j.neulet.2005.05.019
  • 26. Keith A. Kwan Cheung 1 , Hassendrini Peiris 1 , Geoffrey Wallace 2 , Olivia J. Holland 1,3 and Murray D. Mitchell. The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids.Int.J.Mol.Sci 2019, 20(23), 6079 PMID:31810321 PMCID:PMC6929011 DOI:10.3390/ijms20236079
  • 27. Morano A, Fanella M, Albini M, Cifelli P, Palma E, Giallonardo AT, Di Bonaventura C. Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects. Neuropsychiatr Dis Treat. 2020 Feb 7;16:381-396. eCollection 2020. Review. PMID: 32103958 DOI: 10.2147/NDT.S203782.
  • 28. Lazarini-Lopes W, Do Val-da Silva RA, da Silva-Júnior RMP, Leite JP, Garcia-Cairasco N. The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: From behavior and mechanisms to clinical insights. Neurosci Biobehav Rev. 2020 Apr;111:166-182. doi: 10.1016/j.neubiorev.2020.01.014. Epub 2020 Jan 16. PMID: 31954723 DOI:10.1016/j.neubiorev.2020.01.014
  • 29. Gaston TE, Szaflarski JP. Cannabis for the Treatment of Epilepsy: an Update. Curr Neurol Neurosci Rep. 2018 Sep 8;18(11):73. Review. PMID: 30194563 DOI:10.1007/s11910-018-0882-y.
  • 30. Suleymanova EM, Shangaraeva VA, van Rijn CM, Vinogradova LV. The cannabinoid receptor agonist WIN55.212 reduces consequences of status epilepticus in rats. Neuroscience. 2016 Oct 15;334:191-200. Epub 2016 Aug 9. PMID: 27520083 DOI: 10.1016/j.neuroscience.2016.08.004

Effects of endocannabinoids in pentylenetetrazole induced seizures in mice

Year 2020, Volume: 4 Issue: 3, 209 - 215, 29.10.2020
https://doi.org/10.30565/medalanya.690410

Abstract

Aim: Pentylenetetrazole (PTZ) is an agent widely used for the assessment of putative anticonvulsant drugs and is supposed to induce repetitive firing of nerve fibers as well as shorten the refractory period. Anandamide is an endocannabinoid synthesized in neurons, excreted by depolarization and inactivated very quickly. Ethanol is a psychoactive substance which has an anti convulsive effect after acute application, although repeated administrations of high doses lead to proconvulsant actions. In order to explore whether endocannabinoids are effective in the treatment of epilepsy or not, we aimed to study the effect of anandamide on PTZ induced epileptic seizures in mice by determining which types of cannabinoid receptors are.

Methods: In our small animal experimental model, thirty-two Swiss albino male mice weighing 25-35 g were used. During the study, the experimental animals were randomly divided into four groups as the control, anandamide, synthetic analogue of anandamide (WIN 55.212-2), and ethanol and the number of epileptic attacks, duration of the first epileptic attack, the total duration of the epileptic attacks and the latency time to the first attack after PTZ injection, mortality and the day of kindling development were compared in each group.


Results:
The mortality rate and seizure duration were significantly lower in all of the anandamide, WIN 55.212-2 and ethanol groups. After pre-PTZ injection of ethanol and anandamide, latency periods were significantly higher, without any difference between the groups. However, a similar relationship was not present between WIN 55.212-2 and ethanol.

Conclusion: Our data showed that the antiepileptic effect of endocannabinoid anandamide observed was due to the its solvent, ethanol; however this effect was not found with its analogue WIN 55.212-2. Although both endocannabinoids resulted in interaction in the cannabinoid receptors, this difference may be the result of their different pharmacokinetics, metabolisms or degradation products and active metabolites.

References

  • 1. German SP, Aıda SV, German SM. Effect of extracellular long-time microperfusion of high concentrations of glutamate and glycine on picrotoxin seizure thresholds in the hippocampus of freely moving rats. Brain Res. 2000; 888: 19-25. PMID:11146048 DOI:10.1016/s0006-8993(00)02974-7
  • 2. Rocha L, Brıones M, Ackermann RF. Pentylenetetrazole-induced kindling:early involvement of excitatory and inhibitory systems. Epilepsy Res. 1996; 26: 105-113. PMID:8985692 DOI:10.1016/s0920-1211(96)00046-0
  • 3. Urushıtanı M, Nakamızo T, Inoue R. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. J Neurosci Res. 2001; 63: 377-387. PMID:11223912 DOI:10.1002/1097-4547
  • 4. Prast H, Phılıppu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2000; 64: 51-68. PMID:11250062 DOI:10.1016/s0301-0082(00)00044-7
  • 5. Osonoe K, Morı N, Suzukı K. Antiepileptic effects of inhibitors of nitric oxide synthase examined in pentylene-tetrazole-induced seizures in rats. Brain Res. 1994; 663: 338-340. PMID:7533045 DOI:10.1016/0006-8993(94)91283-1
  • 6. Devane W.A, Hanus L, Breuer A, Pertwe R.G, Stevenson L.A, Gerlin G, Gibson D, Mandembaum A, Ettinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to cannabinoid receptor. Science. 1992; 258: 1946-1949. PMID:1470919 DOI:10.1126/science.1470919
  • 7. Hanus L, Gopher A, Almog S, Mechoulam R. Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J. Med. Chem. 1993; 36: 3032-3034. PMID:8411021 DOI:10.1021/jm00072a026
  • 8. Felder C.C, Nielsen A, Briley E.M, Palkovits M, Priller J, Axelrod J, Nuguyen D.N, Richardson J.M, Riggin R.M, Coppel G.A, Paul S.M, Becker G.W. Isolation and measurement of the endogenous canabinoid receptor antagonist in the brain and peripheral tissues of human and rat. FEBS. Lett. 1996; 393: 231-5. PMID:8814296 DOI:10.1016/0014-5793(96)00891-5
  • 9. Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur. J. Pharmacol. 1998; 359: 1-18. PMID: 9831287 DOI: 10.1016/s0014-2999(98)00649-9
  • 10. Felder C. C, Briley E. M, Axelrod J. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 7656-7660. PMID:8395053PMCID:PMC47201 DOI:10.1073/pnas.90.16.7656
  • 11. Mackıe K, Devane W. A, Hılle B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol. Pharmacol. 1993; 44: 498-503. PMID:8371711
  • 12. Pertwee R. G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997; 4: 129-180. PMID:9336020 DOI:10.1016/s0163-7258(97)82001-3
  • 13. Hansen H. S, Moesgaard B, Hansen H. H, Schousboe A, Petersen G. Formation of N-acyl-phosphatidylethanolamine and N-acyl-etholamine (including anandamide) during glutamate-induced neurotoxicity. Lipids. 1999; 34: 327-330. PMID:10419193 DOI:10.1007/bf02562333
  • 14. Hansen H. H. Anandamide, but not 2-arachidonylglycerol, accumulates during in vivo neurodegeneration. J Neurochem. 2001; 78: 1415-1427. PMID:11579150 DOI:10.1046/j.1471-4159.2001.00542.x
  • 15. Sinor A. D, Irvin S. M, Greenberg D. A. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett. 2000; 278: 157-160. PMID:10653017 DOI:10.1016/s0304-3940(99)00922-2
  • 16. Nagayama T, Sinor A. D, Simon R. P, Chen J, Graham S. H, Jin K, Greenberg D. A. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999; 19: 2987-2995. PMID:10191316 PMCID:PMC6782289
  • 17. Mechoulam R. Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):93-9. PMID:12052029 DOI:10.1054/plef.2001.0340
  • 18. Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998; 21: 521-528. PMID:9881850 DOI:10.1016/s0166-2236(98)01283-1
  • 19. Piomelli D, Beltramo M, Glasnapp S. Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci USA. 1999; 96: 5802-5807. PMID:10318965 PMCID:PMC21941 DOI:10.1073/pnas.96.10.5802
  • 20. Di Marzo V. Biosynthesis and inactivation of endocannabinoids:relevance to their proposed role as neuromodulators. Life Sci. 1999; 65: 645-655. PMID:10462065 DOI:10.1016/s0024-3205(99)00287-8
  • 21. Hillard C. J, Jarrahian A. The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids. 2000; 108: 123-124 PMID:11106786 DOI:10.1016/s0009-3084(00)00191-2
  • 22. Maccarrone M, Van Der Stelt M, Rossi A, Veldink G. A, Vliegenthart J. F. G, Finazzi Agro A. Anandamide hydrolysis by human cells in culture and brain. J Biol Chem. 1998; 273: 32332-32339. PMID:9822713 DOI:10.1074/jbc.273.48.32332
  • 23. Ueda N, Puffenbarger R. A, Yamamoto S. Deutsch D. G. The fatty acid amide hydrolase (FAAH). Chem Phys. 2000; 108: 107-121. PMID:11106785 DOI:10.1016/s0009-3084(00)00190-0
  • 24. Steffens M, Schulze-Bonhage A, Surges R, Feuerstein TJ. Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids. Neurosci Lett. 2005 Sep 2;385(1):13-7. PMID: 15923084 DOI: 10.1016/j.neulet.2005.05.019
  • 25. Steffens M, Schulze-Bonhage A, Surges R, Feuerstein TJ. Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids.Neurosci Lett. 2005 May. PMID:15923084 DOI:10.1016/j.neulet.2005.05.019
  • 26. Keith A. Kwan Cheung 1 , Hassendrini Peiris 1 , Geoffrey Wallace 2 , Olivia J. Holland 1,3 and Murray D. Mitchell. The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids.Int.J.Mol.Sci 2019, 20(23), 6079 PMID:31810321 PMCID:PMC6929011 DOI:10.3390/ijms20236079
  • 27. Morano A, Fanella M, Albini M, Cifelli P, Palma E, Giallonardo AT, Di Bonaventura C. Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects. Neuropsychiatr Dis Treat. 2020 Feb 7;16:381-396. eCollection 2020. Review. PMID: 32103958 DOI: 10.2147/NDT.S203782.
  • 28. Lazarini-Lopes W, Do Val-da Silva RA, da Silva-Júnior RMP, Leite JP, Garcia-Cairasco N. The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: From behavior and mechanisms to clinical insights. Neurosci Biobehav Rev. 2020 Apr;111:166-182. doi: 10.1016/j.neubiorev.2020.01.014. Epub 2020 Jan 16. PMID: 31954723 DOI:10.1016/j.neubiorev.2020.01.014
  • 29. Gaston TE, Szaflarski JP. Cannabis for the Treatment of Epilepsy: an Update. Curr Neurol Neurosci Rep. 2018 Sep 8;18(11):73. Review. PMID: 30194563 DOI:10.1007/s11910-018-0882-y.
  • 30. Suleymanova EM, Shangaraeva VA, van Rijn CM, Vinogradova LV. The cannabinoid receptor agonist WIN55.212 reduces consequences of status epilepticus in rats. Neuroscience. 2016 Oct 15;334:191-200. Epub 2016 Aug 9. PMID: 27520083 DOI: 10.1016/j.neuroscience.2016.08.004
There are 30 citations in total.

Details

Primary Language English
Subjects Surgery
Journal Section Research Article
Authors

Engin Yücel 0000-0001-8910-5359

Zühal Aktuna This is me 0000-0002-7429-9696

İsmail Semih Keskil This is me 0000-0003-0891-2605

Publication Date October 29, 2020
Submission Date February 17, 2020
Acceptance Date May 30, 2020
Published in Issue Year 2020 Volume: 4 Issue: 3

Cite

Vancouver Yücel E, Aktuna Z, Keskil İS. Effects of endocannabinoids in pentylenetetrazole induced seizures in mice. Acta Med. Alanya. 2020;4(3):209-15.

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