PATHOPHYSIOLOGY OF EPILEPTOGENESIS: A COMPREHENSIVE REVIEW

Main Article Content

Sachin Gulia
Vipin kumar
Megha Thakur
Dr Ashwani Kumar

Keywords

Epileptogenesis, Epilepsy, Neurotransmitters, Pathophysiology, Signaling

Abstract

There are several neurological disorders that can cause recurrent seizures. Epilepsy is one of them, and is characterized by a persistent predisposition to seizures caused by abnormal neuronal activity in the brain. The relative imbalance between excitatory and inhibitory neurotransmitters may result in epileptic seizures. Pathogenesis of epilepsy can be influenced by changes in the expression of receptors and ion channels regulated by neurotransmitters. A neurotransmitter metabolism error affects the synthesis, breakdown, transport or the cofactors of neurotransmitters. The impairment of neuronal receptors, intracellular signaling, vesicle release, or other synaptic abnormalities can also cause neurotransmitter dysfunction. The main clinical hallmark of some diseases is epilepsy. The purpose of this comprehensive review is to describe the epileptogenic mechanisms as well as the implications arising from mutations in neurotransmitter-mediated receptors and ion channels in epilepsy.

Abstract 321 | pdf Downloads 152

References

1. Akyuz, E., Polat, A. K., Eroglu, E., Kullu, I., Angelopoulou, E., &Paudel, Y. N. (2021). Revisiting the role of neurotransmitters in epilepsy: An updated review. Life sciences, 265, 118826.
2. Arafa, N. M., Abdel-Rahman, M., El-khadragy, M. F., &Kassab, R. B. (2013). Evaluation of the possible epileptogenic activity of ciprofloxacin: the role of Nigella sativa on amino acids neurotransmitters. Neurochemical research, 38, 174-185.
3. Atabaki, R., Khaleghzadeh-Ahangar, H., Esmaeili, N., &Mohseni-Moghaddam, P. (2023). Role of pyroptosis, a pro-inflammatory programmed cell death, in epilepsy. Cellular and Molecular Neurobiology, 43(3), 1049-1059.
4. Aulická, S., Česká, K., Šána, J., Siegl, F., Brichtová, E., Ošlejšková, H., ...&Nestrašil, I. (2022). Cytokine-chemokine profiles in the hippocampus of patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Epilepsy Research, 180, 106858.
5. Beghi, E., Giussani, G., Costa, C., DiFrancesco, J. C., Dhakar, M., Leppik, I., ...& ILAE Task Force on Epilepsy in the Elderly (2017–2021). (2023). The epidemiology of epilepsy in older adults: A narrative review by the ILAE Task Force on Epilepsy in the Elderly. Epilepsia.
6. Begley, C., Wagner, R. G., Abraham, A., Beghi, E., Newton, C., Kwon, C. S., ...& Winkler, A. S. (2022). The global cost of epilepsy: a systematic review and extrapolation. Epilepsia, 63(4), 892-903.
7. Brennan, G. P., &Henshall, D. C. (2018). microRNAs in the pathophysiology of epilepsy. Neuroscience letters, 667, 47-52.
8. Castañeda-Cabral, J. L., Ureña-Guerrero, M. E., Beas-Zárate, C., Colunga-Durán, A., Nuñez-Lumbreras, M. D. L. A., Orozco-Suárez, S., ...& Rocha, L. (2020). Increased expression of proinflammatory cytokines and iNOS in the neocortical microvasculature of patients with temporal lobe epilepsy. Immunologic Research, 68, 169-176.
9. Chaunsali, L., Tewari, B. P., &Sontheimer, H. (2021). Perineuronal net dynamics in the pathophysiology of epilepsy. Epilepsy Currents, 21(4), 273-281.
10. Chen, Yu, Marwa M. Nagib, NelufarYasmen, Madison N. Sluter, Taylor L. Littlejohn, Ying Yu, and Jianxiong Jiang. "Neuroinflammatory mediators in acquired epilepsy: an update." Inflammation Research 72, no. 4 (2023): 683-701.
11. Chiprés-Tinajero, G. A., Núñez-Ochoa, M. A., & Medina-Ceja, L. (2021). Increased immunoreactivity of glutamate receptors, neuronal nuclear protein and glial fibrillary acidic protein in the hippocampus of epileptic rats with fast ripple activity. Experimental Brain Research, 239(6), 2015-2024.
12. Cingolani, L. A., Vitale, C., &Dityatev, A. (2019). Intra-and extracellular pillars of a unifying framework for homeostatic plasticity: a crosstalk between metabotropic receptors and extracellular matrix. Frontiers in Cellular Neuroscience, 13, 513.
13. Cui, Z., Zhang, X., Song, H., Yang, F., Feng, S., Feng, L., ...&Xu, B. (2019). Differential long non-coding RNA (lncRNA) profiles associated with hippocampal sclerosis in human mesial temporal lobe epilepsy. International Journal of Clinical and Experimental Pathology, 12(1), 259.
14. Devi, P. U., Manocha, A., &Vohora, D. (2008). Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers. Expert Opinion on Pharmacotherapy, 9(18), 3169-3177.
15. Dhaher, R., Gruenbaum, S. E., Sandhu, M. R. S., Ottestad-Hansen, S., Tu, N., Wang, Y., ...& Eid, T. (2021). Network-related changes in neurotransmitters and seizure propagation during rodent epileptogenesis. Neurology, 96(18), e2261-e2271.
16. Engelborghs, S., D’hooge, R., & De Deyn, P. P. (2000). Pathophysiology of epilepsy. Actaneurologicabelgica, 100(4), 201-213.
17. Falco-Walter, J. (2020, December). Epilepsy—definition, classification, pathophysiology, and epidemiology. In Seminars in neurology (Vol. 40, No. 06, pp. 617-623). Thieme Medical Publishers, Inc..
18. Frantseva, M. V., Velazquez, J. P., Tsoraklidis, G., Mendonca, A. J., Adamchik, Y., Mills, L. R., ... & Burnham, M. W. (2000). Oxidative stress is involved in seizure-induced neurodegeneration in the kindling model of epilepsy. Neuroscience, 97(3), 431-435.
19. Fukuyama, K., & Okada, M. (2022). Brivaracetam and levetiracetam suppress astroglial l-glutamate release through hemichannel via inhibition of synaptic vesicle protein. International Journal of Molecular Sciences, 23(9), 4473.
20. Fukuyama, K., & Okada, M. (2022). High frequency oscillations play important roles in development of epileptogenesis/ictogenesis via activation of astroglialsignallings. Biomedicine & Pharmacotherapy, 149, 112846.
21. Fukuyama, K., Fukuzawa, M., Shiroyama, T., & Okada, M. (2020). Pathogenesis and pathophysiology of autosomal dominant sleep‐related hypermotor epilepsy with S284L‐mutant α4 subunit of nicotinic ACh receptor. British Journal of Pharmacology, 177(9), 2143-2162.
22. Gasparini, S., Ferlazzo, E., Sueri, C., Cianci, V., Ascoli, M., Cavalli, S. M., ...& Epilepsy Study Group of the Italian Neurological Society. (2019). Hypertension, seizures, and epilepsy: a review on pathophysiology and management. Neurological Sciences, 40, 1775-1783.
23. Geronzi, U., Lotti, F., &Grosso, S. (2018). Oxidative stress in epilepsy. Expert Review of Neurotherapeutics, 18(5), 427-434.
24. Godinho, A. M. G. (2021). Exploring the activation of NLRP3 inflammasome by reactive oxygen species (ROS) in a model of epileptogenesis (Doctoral dissertation).
25. Golub, V., & Reddy, S. (2020). Anatomical Basis of Epileptogenesis in a Mouse Model of Traumatic Brain Injury. The FASEB Journal, 34(S1), 1-1.
26. Jacob, J. (2016). Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders. Epilepsia, 57(2), 182-193.
27. Kłodzińska, A., Chojnacka-Wójcik, E., &Pilc, A. (1999). Selective group II glutamate metabotropic receptor agonist LY354740 attenuates pentetrazole-and picrotoxin-induced seizures. Polish journal of pharmacology, 51(6), 543-545.
28. Korotkov, A., Broekaart, D. W., Banchaewa, L., Pustjens, B., van Scheppingen, J., Anink, J. J., ... &Aronica, E. (2020). microRNA‐132 is overexpressed in glia in temporal lobe epilepsy and reduces the expression of pro‐epileptogenic factors in human cultured astrocytes. Glia, 68(1), 60-75.
29. Kovalenko, A. A., Zakharova, M. V., Schwarz, A. P., Dyomina, A. V., Zubareva, O. E., &Zaitsev, A. V. (2022). Changes in Metabotropic Glutamate Receptor Gene Expression in Rat Brain in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy. International Journal of Molecular Sciences, 23(5), 2752.
30. Kovalenko, A. A., Zakharova, M. V., Schwarz, A. P., Dyomina, A. V., Zubareva, O. E., &Sarnat, H. B., & Flores-Sarnat, L. (2021). Excitatory/inhibitory synaptic ratios in polymicrogyria and down syndrome help explain epileptogenesis in malformations. Pediatric Neurology, 116, 41-54.
31. Lang, J. D., &Hamer, H. M. (2022). Epidemiology of epilepsy in old age–English Version. ZeitschriftfürEpileptologie, 1-4.
32. Mastrangelo, M. (2021). Epilepsy in inherited neurotransmitter disorders: Spotlights on pathophysiology and clinical management. Metabolic Brain Disease, 36(1), 29-43.
33. Mathern, G. W., Mendoza, D., Lozada, A., Pretorius, J. K., Dehnes, Y., Danbolt, N. C., ... &Adelson, P. D. (1999). Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology, 52(3), 453-453.
34. 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. Oxidative medicine and cellular longevity, 2014.
35. Meng, F., & Yao, L. (2020). The role of inflammation in epileptogenesis . ActaEpileptologica, 2(1), 1-19.
36. Moore, J. L., Carvalho, D. Z., St Louis, E. K., &Bazil, C. (2021). Sleep and epilepsy: a focused review of pathophysiology, clinical syndromes, co-morbidities, and therapy. Neurotherapeutics, 18, 170-180.
37. Needs, H. I., Henley, B. S., Cavallo, D., Gurung, S., Modebadze, T., Woodhall, G., & Henley, J. M. (2019). Changes in excitatory and inhibitory receptor expression and network activity during induction and establishment of epilepsy in the rat Reduced Intensity Status Epilepticus (RISE) model. Neuropharmacology, 158, 107728.
38. Numis, A. L., Foster-Barber, A., Deng, X., Rogers, E. E., Barkovich, A. J., Ferriero, D. M., & Glass, H. C. (2019). Early changes in pro-inflammatory cytokine levels in neonates with encephalopathy are associated with remote epilepsy. Pediatric research, 86(5), 616-621.
39. Palma, E., Ruffolo, G., Cifelli, P., Roseti, C., Vliet, E. A. V., &Aronica, E. (2017). Modulation of GABAA Receptors in the Treatment of Epilepsy. Current pharmaceutical design, 23(37), 5563-5568.
40. Patel, D. C., Tewari, B. P., Chaunsali, L., &Sontheimer, H. (2019). Neuron–glia interactions in the pathophysiology of epilepsy. Nature Reviews Neuroscience, 20(5), 282-297.
41. PATEL, M., & WALKER, M. (2022). METABOLISM, REACTIVE OXYGEN SPECIES, AND EPILEPSY. Neurobiology of the Epilepsies: From Epilepsy: A Comprehensive Textbook.
42. Puttachary, S., Sharma, S., Stark, S., &Thippeswamy, T. (2015). Seizure-induced oxidative stress in temporal lobe epilepsy. BioMed research international, 2015.
43. Qian, F., & Tang, F. R. (2016). Metabotropic glutamate receptors and interacting proteins in epileptogenesis. Current Neuropharmacology, 14(5), 551-562.
44. Roma-Mateo, C., Aguado, C., García-Giménez, J. L., Knecht, E., Sanz, P., &Pallardo, F. V. (2015). Oxidative stress, a new hallmark in the pathophysiology of Lafora progressive myoclonus epilepsy. Free Radical Biology and Medicine, 88, 30-41.
45. Rossi, J., Cavallieri, F., Biagini, G., Rizzi, R., Russo, M., Cozzi, S., ...&Valzania, F. (2022). Epileptogenesis and Tumorigenesis in Glioblastoma: Which Relationship?. Medicina, 58(10), 1349.
46. Russo, M. E. (1981). The pathophysiology of epilepsy. The Cornell Veterinarian, 71(2), 221-247.
47. Sandhu, M. R. S., Gruenbaum, B. F., Gruenbaum, S. E., Dhaher, R., Deshpande, K., Funaro, M. C., ...& Eid, T. (2021). Astroglial glutamine synthetase and the pathogenesis of mesial temporal lobe epilepsy. Frontiers in neurology, 12, 665334.
48. Sandhu, M. R. S., Gruenbaum, B. F., Gruenbaum, S. E., Dhaher, R., Deshpande, K., Funaro, M. C., ...& Eid, T. (2021). Astroglial glutamine synthetase and the pathogenesis of mesial temporal lobe epilepsy. Frontiers in neurology, 12, 665334.
49. Sano, F., Shigetomi, E., Shinozaki, Y., Tsuzukiyama, H., Saito, K., Mikoshiba, K., ...& Koizumi, S. (2021). Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus. JCI insight, 6(9).
50. Santos, V. R., Tilelli, C. Q., Fernandes, A., de Castro, O. W., Del-Vecchio, F., & Garcia-Cairasco, N. (2023). Different types of Status Epilepticus may lead to similar hippocampal epileptogenesis processes. IBRO Neuroscience Reports.
51. Sarikaya, I. (2015). PET studies in epilepsy. American journal of nuclear medicine and molecular imaging, 5(5), 416.
52. Sarlo, G. L., & Holton, K. F. (2021). Brain concentrations of glutamate and GABA in human epilepsy: A review. Seizure, 91, 213-227.
53. Sarnat, H. B., & Flores-Sarnat, L. (2021). Excitatory/inhibitory synaptic ratios in polymicrogyria and down syndrome help explain epileptogenesis in malformations. Pediatric Neurology, 116, 41-54.
54. Sears, S. M., & Hewett, S. J. (2021). Influence of glutamate and GABA transport on brain excitatory/inhibitory balance. Experimental Biology and Medicine, 246(9), 1069-1083.
55. Sgadò, P., Dunleavy, M., Genovesi, S., Provenzano, G., &Bozzi, Y. (2011). The role of GABAergic system in neurodevelopmental disorders: a focus on autism and epilepsy. International journal of physiology, pathophysiology and pharmacology, 3(3), 223.
56. Sharma, R., Leung, W. L., Zamani, A., O’brien, T. J., Casillas Espinosa, P. M., &Semple, B. D. (2019). Neuroinflammation in post-traumatic epilepsy: pathophysiology and tractable therapeutic targets. Brain sciences, 9(11), 318.
57. SoltaniKhaboushan, A., Yazdanpanah, N., &Rezaei, N. (2022). Neuroinflammation and proinflammatory cytokines in epileptogenesis. Molecular Neurobiology, 59(3), 1724-1743.
58. Song, L. J., Zhang, H., Jin, J. G., Wang, C., Qu, X. P., Jiang, X., ...&Shen, L. L. (2020). Rho-associated Protein Kinase 2 Confers Epileptogenesis through the Activation of Astroglial Stat3 Pathway.
59. Song, L. J., Zhang, H., Qu, X. P., Jin, J. G., Wang, C., Jiang, X., ... & Liu, B. (2022). Increased expression of Rho-associated protein kinase 2 confers astroglial Stat3 pathway activation during epileptogenesis. Neuroscience Research, 177, 25-37.
60. Tekgul, H., Serin, H. M., Simsek, E., Kanmaz, S., Gazeteci, H., Azarsiz, E., ...&Gokben, S. (2020). CSF levels of a set of neurotrophic factors (brain-derived neurotrophic factor, nerve growth factor) and neuropeptides (neuropeptide Y, galanin) in epileptic children. Journal of Clinical Neuroscience, 76, 41-45.
61. Tekgul, H., Simsek, E., Erdoğan, M. A., Yiğittürk, G., Erbaş, O., &Taşkıran, D. (2020). The potential effects of anticonvulsant drugs on neuropeptides and neurotrophins in pentylenetetrazol kindled seizures in the rat. International Journal of Neuroscience, 130(2), 193-203.
62. Terrone, G., Balosso, S., Pauletti, A., Ravizza, T., &Vezzani, A. (2020). Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology, 167, 107742.
63. Terrone, G., Frigerio, F., Balosso, S., Ravizza, T., &Vezzani, A. (2019). Inflammation and reactive oxygen species in status epilepticus: Biomarkers and implications for therapy. Epilepsy &Behavior, 101, 106275.
64. Verhoog, Q. P., Holtman, L., Aronica, E., & van Vliet, E. A. (2020). Astrocytes as guardians of neuronal excitability: mechanisms underlying epileptogenesis. Frontiers in Neurology, 11, 591690.
65. Vezzani, A., Balosso, S., &Ravizza, T. (2008). The role of cytokines in the pathophysiology of epilepsy. Brain, behavior, and immunity, 22(6), 797-803.
66. Victor, T. R., &Tsirka, S. E. (2020). Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy. Neuroimmunology and neuroinflammation, 7, 234.
67. Vishwakarma, S., Singh, S., & Singh, T. G. (2022). Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis. Molecular Biology Reports, 1-16.
68. Walker, M. C. (2023). Reactive oxygen species in status epilepticus. Epilepsia Open, 8, S66-S72.
69. Wang, N., Wang, D., Zhou, H., Xu, C., Hu, X., Qian, Z., &Xu, X. (2021). Serum neuropeptide Y level is associated with post-ischemic stroke epilepsy. Journal of Stroke and Cerebrovascular Diseases, 30(2), 105475.
70. Wasterlain, C. G., Fujikawa, D. G., Penix, L., &Sankar, R. (1993). Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia, 34, S37-S53.
71. Wong, R. K., Chuang, S. C., & Bianchi, R. (2002). Metabotropic glutamate receptors and epileptogenesis. Epilepsy Currents, 2(3), 81-85.
72. Xu, X. X., Shi, R. X., Fu, Y., Wang, J. L., Tong, X., Zhang, S. Q., ... &Guo, F. (2022). Neuronal nitric oxide synthase/reactive oxygen species pathway is involved in apoptosis and pyroptosis in epilepsy. Neural Regeneration Research.
73. Yang, T. T., Qian, F., Liu, L., Peng, X. C., Huang, J. R., Ren, B. X., & Tang, F. R. (2021). Astroglialconnexins in epileptogenesis. Seizure, 84, 122-128.
74. Yazdanpanah, N., &Rezaei, N. (2022). Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis. Molecular Neurobiology.
75. Yeo, X. Y., Cunliffe, G., Ho, R. C., Lee, S. S., & Jung, S. (2022). Potentials of neuropeptides as therapeutic agents for neurological diseases. Biomedicines, 10(2), 343.