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:: Volume 28, Issue 1 (Scientific Journal of Kurdistan University of Medical Sciences 2023) ::
SJKU 2023, 28(1): 30-39 Back to browse issues page
Investigating the Synergistic Effect of Palmitoylethanolamide and Ganaxolone in PTZ-induced Tonic-clonic Seizures
Hesamodin Bagheripoor1 , Abbas Alimoradian2 , Mehdi Sadegh3
1- Medical student, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
2- Associate Professor, Department of Pharmacology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
3- Associate Professor, Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran , msadegh1360@yahoo.com
Abstract:   (1497 Views)
Background and Aim: Anticonvulsive effects of neurosteroids were shown in animal models. Endocannabinoids modulate neuronal excitability. In this study, we investigated the synergism of the simultaneous application of Palmitoylethanolamide (PEA) as an endocannabinoid and Ganaxolone as a neurosteroid, on tonic-clonic seizures induced by PTZ. 
Materials and Methods: Adult male Wistar rats were used. The tonic-colonic seizure was induced through a single injection of PTZ (80 mg/kg) and seizure stages were monitored for 30 minutes. Ganaxolone (10 mg/kg) and PEA (40 mg/kg) dissolved in DMSO were injected alone and simultaneously intra-peritoneal 15 minutes before the PTZ injection. Delay to the seizure stages, duration of the stages, and mortality due to seizures were measured.
Results: PEA had no significant effect on seizure indices. Ganaxolone significantly increased delay to seizure stages 1-4 and reduced the duration of stage 5, also mortality of seizures was reduced in comparison with PTZ group from 50% to 16%.  Simultaneous injection of PEA and Ganaxolone significantly delayed seizure stages 1-5 in comparison with both PTZ and Ganaxolone groups and reduced the duration of stage 5. Also, mortality due to seizures was reduced in comparison with PTZ group from 50% to 0%.
Conclusion: PEA injection with Ganaxolone increased the anticonvulsive effects of Ganaxolone, and reduced mortality due to seizures.   
Keywords: Anandamide, Endocannabinoid, Epilepsy, Neurosteroid
Full-Text [PDF 664 kb]   (625 Downloads)    
Type of Study: Original Research | Subject: Physiology and neurosciences
Received: 2021/10/2 | Accepted: 2021/11/7 | Published: 2023/03/15
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37. Reddy DS, Rogawski MA. Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. Epilepsy Res. 2010;89(2-3):254-60.
38. Biagini G, Longo D, Baldelli E, Zoli M, Rogawski MA, Bertazzoni G, et al. Neurosteroids and epileptogenesis in the pilocarpine model: evidence for a relationship between P450scc induction and length of the latent period. Epilepsia. 2009;50 Suppl 1:53-8.
39. Banerjee PN, Filippi D, Hauser WA. The descriptive epidemiology of epilepsy—a review. Epilepsy research. 2009;85(1):31-45.
40. Navidhamidi M, Ghasemi M, Mehranfard N. Epilepsy-associated alterations in hippocampal excitability. Rev Neurosci. 2017;28(3):307-34.
41. Engelborghs S, D'Hooge R, De Deyn PP. Pathophysiology of epilepsy. Acta Neurol Belg. 2000;100(4):201-13.
42. Iannotti FA, Di Marzo V, Petrosino S. Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders. Prog Lipid Res. 2016;62:107-28.
43. 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(3):939-48.
44. Stasiulewicz A, Znajdek K, Grudzien M, Pawinski T, Sulkowska AJI. A Guide to Targeting the Endocannabinoid System in Drug Design. Int J Mol Sci. 2020;21(8).
45. Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today. 2017;22(1):105-10.
46. Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020;16(1):9-29.
47. Farrelly AM, Vlachou S, Grintzalis K. Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances. Int J Environ Res Public Health. 2021;18(8).
48. Katona I. Cannabis and Endocannabinoid Signaling in Epilepsy. Handb Exp Pharmacol. 2015;231:285-316.
49. Millan-Guerrero RO, Isais-Millan S. Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies. Gac Med Mex. 2019;155(5):471-4.
50. Gholami M, Amri J, Pazhoohan S, Sadegh M. Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor. J Complement Integr Med. 2021.
51. Senn L, Cannazza G, Biagini G. Receptors and Channels Possibly Mediating the Effects of Phytocannabinoids on Seizures and Epilepsy. Pharmaceuticals (Basel). 2020;13(8).
52. Skaper SD, Facci L, Giusti P. Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. Mol Neurobiol. 2013;48(2):340-52.
53. Scuderi C, Valenza M, Stecca C, Esposito G, Carratu MR, Steardo L. Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-alpha. J Neuroinflammation. 2012;9:49.
54. Aghaei I, Rostampour M, Shabani M, Naderi N, Motamedi F, Babaei P, et al. Palmitoylethanolamide attenuates PTZ-induced seizures through CB1 and CB2 receptors. Epilepsy Res. 2015;117:23-8.
55. Citraro R, Russo E, Scicchitano F, van Rijn CM, Cosco D, Avagliano C, et al. Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-alpha receptor activation in a genetic model of absence epilepsy. Neuropharmacology. 2013;69:115-26.
56. Post JM, Loch S, Lerner R, Remmers F, Lomazzo E, Lutz B, et al. Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy. Front Mol Neurosci. 2018;11:67.
57. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol. 2006;13(3):277-82.
58. Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf. 2007;30(7):555-67.
59. Smith SS, Shen H, Gong QH, Zhou X. Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits. Pharmacol Ther. 2007;116(1):58-76.
60. Biagini G, Baldelli E, Longo D, Pradelli L, Zini I, Rogawski MA, et al. Endogenous neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy. Exp Neurol. 2006;201(2):519-24.
61. Lattanzi S, Riva A, Striano P. Ganaxolone treatment for epilepsy patients: from pharmacology to place in therapy. Expert Rev Neurother. 2021:1-16.
62. Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 2011;20(5):359-68.
63. Veliskova J. Behavioral characterization of seizures in rats. Models of seizures and epilepsy Elsevier Academic Press, Burlington. 2006:601-11.
64. Sadegh M, Sakhaie MH. Carvacrol mitigates proconvulsive effects of lipopolysaccharide, possibly through the hippocampal cyclooxygenase-2 inhibition. Metab Brain Dis. 2018;33(6):2045-50.
65. Reddy DS, Rogawski MA. Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther. 2000;295(3):1241-8.
66. Mattace Raso G, Russo R, Calignano A, Meli R. Palmitoylethanolamide in CNS health and disease. Pharmacol Res. 2014;86:32-41.
67. Sheerin AH, Zhang X, Saucier DM, Corcoran ME. Selective antiepileptic effects of N-palmitoylethanolamide, a putative endocannabinoid. Epilepsia. 2004;45(10):1184-8.
68. Zareie P, Sadegh M, Palizvan M. The Effect of 2-Archidonyl Glycerol (2-AG) as an Endocannabinoid on Tonic- Clonic Seizures Induced by Pentylenetetrazol (PTZ). ZUMS Journal. 2017;25(109):11-22.
69. Zareie P, Sadegh M, Palizvan M. Investigating the effect of enzymatic elimination of endocannabinoids inhibitors on tonic- colonic seizure provoked by PTZ. Journal of Babol University Of Medical Sciences. 2016;18(12):49-56.
70. Zareie P, Sadegh M, Moradi-Chameh H. 2-Arachidonoylglycerol enrichment Reduced Epileptiform Activity of the Rat Hippocampus induced with Pentylenetetrazol. Journal of Advances in Medical and Biomedical Research. 2018;26(118):21-7.
71. Loscher W. Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs. Neurochem Res. 2017;42(7):1873-88.
72. MA R, DS R. Neurosteroids: endogenous modulators of seizure susceptibility. Epilepsy: scientific foundations of clinical practice. 2004:319-55.
73. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci. 2005;6(7):565-75.
74. Monaghan EP, Navalta LA, Shum L, Ashbrook DW, Lee DA. Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity. Epilepsia. 1997;38(9):1026-31.
75. Reddy DS, Rogawski MA. Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. Epilepsy Res. 2010;89(2-3):254-60.
76. Biagini G, Longo D, Baldelli E, Zoli M, Rogawski MA, Bertazzoni G, et al. Neurosteroids and epileptogenesis in the pilocarpine model: evidence for a relationship between P450scc induction and length of the latent period. Epilepsia. 2009;50 Suppl 1:53-8.
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Bagheripoor H, Alimoradian A, Sadegh M. Investigating the Synergistic Effect of Palmitoylethanolamide and Ganaxolone in PTZ-induced Tonic-clonic Seizures. SJKU 2023; 28 (1) :30-39
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Volume 28, Issue 1 (Scientific Journal of Kurdistan University of Medical Sciences 2023) Back to browse issues page
مجله علمی دانشگاه علوم پزشکی کردستان Scientific Journal of Kurdistan University of Medical Sciences
مجله علمی دانشگاه علوم پزشکی کردستان Scientific Journal of Kurdistan University of Medical Sciences
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