MANAGING EPILEPSY BY MODULATING GLIA

Abstract

Antiepileptic drugs suppress epileptic seizures and provide a symptomatic control of seizures rather than anti-epileptogenic effects. Evidence about links between glial functions and neuronal signaling has been accumulating and has opened a perspective for the development of anti-epileptogenic approaches for the management of convulsive and non-convulsive forms of epilepsy. Astrocytic excitability and glial transmission have been shown to play critical roles in epileptogenesis and seizure generation. Although glial cells in convulsive types of epilepsy have been widely studied, little work has been done on the contribution of these cells in the non-convulsive epilepsy forms, particularly in absence epilepsy. This review underlies the participation of reactive astrocytes, glia modulating approaches and the roles of inflammatory cytokines in the modulation of convulsive and non-convulsive forms of epilepsy. The understanding of links between astrocyte functions and neuronal signaling in epileptogenesis will be one of the top epilepsy research advances in the future.

Keywords

• antiepileptic
• astrocyte
• epileptogenic
• microglia
• seizure

References

1. Galanopoulou AS, Buckmaster PS, Staley KJ, Moshe SL, Perucca E,
2. Engel J Jr, Loscher W, Noebels JL, Pitkanen A, Stables J, White HS,
3. O’Brien TJ, Simonato M; American Epilepsy Society Basic Science
4. Committee and The International League Against Epilepsy
5. Working Group on Recommendations for Preclinical Epilepsy
6. Drug Discovery. Identification of new epilepsy treatments: issues in
7. preclinical methodology. Epilepsia 2012;53:571–82.
8. Kaminski RM, Rogawski MA, Klitgaard H. The potential of antiseizure

9. drugs and agents that act on novel molecular targets as
10. antiepileptogenic treatments. Neurotherapeutics 2014;11:385–400.
11. Pitkanen A, Nehlig A, Brooks-Kayal AR, Dudek FE, Friedman D,
12. Galanopoulou AS, Jensen FE, Kaminski RM, Kapur J, Klitgaard H,
13. Loscher W, Mody I, Schmidt D. Issues related to development of
14. antiepileptogenic therapies. Epilepsia 2013;54:35–43.
15. Weaver DF. Design of innovative therapeutics for pharmacoresistant
16. epilepsy: challenges and needs. Epilepsia 2013;54:56–9.
17. Loscher W, Brandt C. Prevention or modification of epileptogenesis
18. after brain insults: experimental approaches and translational
19. research. Pharmacol Rev 2010;62:668–700.
20. Gaitatzis A, Sander JW. The mortality of epilepsy revisited.
21. Epileptic Disord 2004;6:3–13.
22. Dambach H, Hinkerohe D, Prochnow N, Stienen MN, Moinfar Z,
23. Haase CG, Hufnagel A, Faustmann PM. Glia and epilepsy: experimental
24. investigation of antiepileptic drugs in an astroglia/microglia
25. co-culture model of inflammation. Epilepsia 2014;55:184–92.
26. Hamby ME, Sofroniew MV. Reactive astrocytes as therapeutic targets
27. for CNS disorders. Neurotherapeutics 2010;7:494–506.
28. Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses:
29. glia, the unacknowledged partner. Trends Neurosci 1999;22:208–15.
30. Coulter DA, Steinhäuser C. Role of astrocytes in epilepsy. Cold
31. Spring Harb Perspect Med 2015;5:a022434.
32. Avoli M, D’Antuono M, Louvel J, Kohling R, Biagini G, Pumain R,
33. D’Arcangelo G, Tancredi V. Network and pharmacological mechanisms
34. leading to epileptiform synchronization in the limbic system in
35. vitro. Prog Neurobiol 2002;68:167–207.
36. Binder DK, Steinhäuser C. Functional changes in astroglial cells in
37. epilepsy. Glia 2006;54:358–68.
38. Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation
39. following pilocarpine-induced seizures in rats. Epilepsia 2008;
40. :33–41.
41. do Nascimento AL, Dos Santos NF, Campos Pelagio F, Aparecida
42. Teixeira S, de Moraes Ferrari EA, Langone F. Neuronal degeneration
43. and gliosis time-course in the mouse hippocampal formation
44. after pilocarpine-induced status epilepticus. Brain Res 2012;1470:
45. –110.
46. Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A. Innate
47. and adaptive immunity during epileptogenesis and spontaneous
48. seizures: evidence from experimental models and human temporal
49. lobe epilepsy. Neurobiol Dis 2008;29:142–60.
50. Rossi AR, Angelo MF, Villarreal A, Lukin J, Ramos AJ. Gabapentin
51. administration reduces reactive gliosis and neurodegeneration after
52. pilocarpine-induced status epilepticus. PLoS One 2013;8:e78516.
53. Crunelli V, Carmignoto G. New vistas on astroglia in convulsive and
54. non-convulsive epilepsy highlight novel astrocytic targets for treatment.
55. J Physiol 2013;591:775–85.
56. Cohen-Gadol AA, Pan JW, Kim JH, Spencer DD, Hetherington
57. HH. Mesial temporal lobe epilepsy: a proton magnetic resonance
58. spectroscopy study and a histopathological analysis. J Neurosurg
59. ;101:613–20.
60. van der Hel WS, Notenboom RG, Bos IW, van Rijen PC, van Veelen
61. CW, de Graan PN. Reduced glutamine synthetase in hippocampal
62. areas with neuron loss in temporal lobe epilepsy. Neurology 2005;64:
63. –33.
64. Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG,
65. Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen
66. O, Gispen WH, de Graan PN. Distribution of glutamate transporters
67. in the hippocampus of patients with pharmaco-resistant temporal
68. lobe epilepsy. Brain 2002;125:32–43.
69. Kong Q, Takahashi K, Schulte D, Stouffer N, Lin Y, Lin CL.
70. Increased glial glutamate transporter EAAT2 expression reduces
71. epileptogenic processes following pilocarpine-induced status epilepticus.
72. Neurobiol Dis 2012;47:145–54.
73. Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M,
74. Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T,
75. Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K. Epilepsy
76. and exacerbation of brain injury in mice lacking the glutamate transporter
77. GLT-1. Science 1997;276:1699–702.
78. Watanabe T, Morimoto K, Hirao T, Suwaki H, Watase K, Tanaka
79. K. Amygdala-kindled and pentylenetetrazole-induced seizures in
80. glutamate transporter GLAST-deficient mice. Brain Res 1999;845:
81. –6.
82. Devinsky O, Vezzani A, Najjar S, de lanerolle N, Rogawski M. Glia
83. and epilepsy: excitability and inflammation. Trends Neurosci 2013;
84. :174–84.
85. Steinhauser C, Grunnet M, Carmignoto G. Crucial role of astrocytes
86. in temporal lobe epilepsy. Neuroscience 2016; 323:157–69.
87. Heuser K, Eid T, Lauritzen F, Thoren AE, Vindedal GF, Tauboll
88. E, Gjerstad L, Spencer DD, Ottersen OP, Nagelhus EA, de
89. Lanerolle NC. Loss of perivascular Kir4.1 potassium channels in the
90. sclerotic hippocampus of patients with mesial temporal lobe epilepsy.
91. J Neuropathol Exp Neurol 2012;71:814–25.
92. Crunelli V, Carmignoto G, Steinhäuser C. Novel astrocyte targets:
93. new avenues for the therapeutic treatment of epilepsy. Neuroscientist
94. ;21:62–83.
95. Buono RJ, Lohoff FW, Sander T, Sperling MR, O’Connor MJ,
96. Dlugos DJ, Ryan SG, Golden GT, Zhao H, Scattergood TM,
97. Berrettini WH, Ferraro TN. Association between variation in the
98. human KCNJ10 potassium ion channel gene and seizure susceptibility.
99. Epilepsy Res 2004;58:175–83.
100. Binder DK, Nagelhus EA, Ottersen OP. Aquaporin-4 and epilepsy.
101. Glia 2012;60:1203–14.
102. Lee DJ, Hsu MS, Seldin MM, Arellano JL, Binder DK. Decreased
103. expression of the glial water channel aquaporin-4 in the intrahippocampal
104. kainic acid model of epileptogenesis. Exp Neurol 2012;
105. :246–55.
106. Alvestad S, Hammer J, Hoddevik EH, Skare Ø, Sonnewald U,
107. Amiry-Moghaddam M, Ottersen OP. Mislocalization of AQP4 precedes
108. chronic seizures in the kainate model of temporal lobe epilepsy.
109. Epilepsy Res 2013;105:30–41.
110. Crunelli V, Leresche N. Childhood absence epilepsy: genes, channels,
111. neurons, and networks. Nat Rev Neurosci 2002;3:371–82.
112. Danober L, Deransart C, Depaulis A, Vergnes M, Marescaux C.
113. Pathophysiological mechanisms of genetic absence epilepsy in the
114. rat. Prog Neurobiol 1998;55:27–57.
115. Vergnes M, Marescaux C, Depaulis A, Micheletti G, Warter JM.
116. Ontogeny of spontaneous petit mal-like seizures in Wistar rats. Brain
117. Res 1986;395:85–7.
118. Errington AC, Cope DW, Crunelli V. Augmentation of tonic
119. GABA(A) inhibition in absence epilepsy: therapeutic value of inverse
120. agonists at extrasynaptic GABA(A) receptors. Adv Pharmacol Sci
121. ;2011:790590.
122. Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug
123. development. Neurotherapeutics 2007;4:18–61.
124. Liu Z , Vergnes M, Depaulis A, Marescaux C. Evidence for a critical
125. role of GABAergic transmission within the thalamus in the genesis
126. and control of absence seizures in the rat. Brain Res 1991;545:1–7.
127. Tolmacheva EA, van Luijtelaar G. Absence seizures are reduced by
128. the enhancement of GABAergic inhibition in the hippocampus in
129. WAG/Rij rats. Neurosci Lett 2007;416:17–21.
130. Touret M, Parrot S, Denoroy L, Belin MF, Didier-Bazes M.
131. Glutamatergic alterations in the cortex of genetic absence epilepsy
132. rats. BMC Neurosci 2007;8:69.
133. Dutuit M, Touret M, Szymocha R, Nehlig A, Belin MF, Didier-
134. Bazes M. Decreased expression of glutamate transporters in genetic
135. absence epilepsy rats before seizure occurrence. J Neurochem 2002;
136. :1029–38.
137. Dutuit M, Didier-Bazes M, Vergnes M, Mutin M, Conjard A,
138. Akaoka H, Belin MF, Touret M. Specific alteration in the expression
139. of glial fibrillary acidic protein, glutamate dehydrogenase, and glutamine
140. synthetase in rats with genetic absence epilepsy. Glia
141. ;32:15–24.
142. Melo TM, Sonnewald U, Touret M, Nehlig A. Cortical glutamate
143. metabolism is enhanced in a genetic model of absence epilepsy. J
144. Cereb Blood Flow Metab 2006;26:1496–1506.
145. Melo TM, Sonnewald U, Bastholm IA, Nehlig A. Astrocytes may
146. play a role in the etiology of absence epilepsy: a comparison between
147. immature GAERS not yet expressing seizures and adults. Neurobiol
148. Dis 2007;28:227–35.
149. Nehlig A, Vergnes M, Marescaux C, Boyet S, Lannes B. Local cerebral
150. glucose utilization in rats with petit mal-like seizures. Ann
151. Neurol 1991;29:72–7.
152. Nehlig A, Vergnes M, Boyet S, Marescaux C. Local cerebral glucose
153. utilization in adult and immature GAERS. Epilepsy Res 1998;32:
154. –12.
155. De Biasi S, Vitellaro-Zuccarello L, Brecha NC. Immunoreactivity
156. for the GABA transporter-1 and GABA transporter-3 is restricted to
157. astrocytes in the rat thalamus. A light and electron microscopic
158. immunolocalization. Neuroscience 1998;83:815–28.
159. Cope DW, Di Giovanni G, Fyson SJ, Orban G, Errington AC,
160. Lorincz ML, Gould TM, Carter DA, Crunelli V. Enhanced tonic
161. GABAA inhibition in typical absence epilepsy. Nat Med
162. ;15:1392–98.
163. Pirttimaki T, Parri HR, Crunelli V. Astrocytic GABA transporter
164. GAT-1 dysfunction in experimental absence seizures. J Physiol
165. ;591:823–33.
166. Yamamura S, Hoshikawa M, Dai K, Saito H, Suzuki N, Niwa O,
167. Okada M. ONO-2506 inhibits spike–wave discharges in a genetic
168. animal model without affecting traditional convulsive tests via gliotransmission
169. regulation. Br J Pharmacol 2013;168:1088–100.
170. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: the profile
171. of a novel anticonvulsant drug-part I: preclinical data. CNS Drug
172. Rev 2007;13:43–56.
173. Vezzani A. Epilepsy and inflammation in the brain: overview and
174. pathophysiology. Epilepsy Curr 2014;14:3–7.
175. Aronica E, Ravizza T, Zurolo E, Vezzani A. Astrocyte immune
176. responses in epilepsy. Glia 2012;60:1258–68.
177. Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A,
178. De Simoni MG, Sperk G, Andell Jonsson S, Lundkvist J, Iverfeldt K,
179. Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist
180. on intracerebral injection and astrocytic overexpression in mice.
181. Proc Natl Acad Sci USA 2000;97:11534–9.
182. Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F,
183. De Simoni MG. Interleukin-1beta immunoreactivity and microglia
184. are enhanced in the rat hippocampus by focal kainate application:
185. functional evidence for enhancement of electrographic seizures. J
186. Neurosci 1999;19:5054–65.
187. Ravizza T, Vezzani A. Status epilepticus induces time-dependent
188. neuronal and astrocytic expression of interleukin-1 receptor type I in
189. the rat limbic system. Neuroscience 2006;137:301–8.
190. Ravizza T, Noe F, Zardoni D, Vaghi V, Sifringer M, Vezzani A.
191. Interleukin converting enzyme inhibition impairs kindling epileptogenesis
192. in rats by blocking astrocytic IL-1beta production.
193. Neurobiol Dis 2008b;31:327–33.
194. Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A. Innate
195. and adaptive immunity during epileptogenesis and spontaneous
196. seizures: evidence from experimental models and human temporal
197. lobe epilepsy. Neurobiol Dis 2008;29:142–60.
198. Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I, Aker
199. RG, Vezzani A, Onat FY. IL-1‚ is induced in reactive astrocytes in
200. the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence.
201. Neurobiol Dis 2011;44:259–69.
202. Carcak N, Aker RG, Ozdemir O, Demiralp T, Onat FY. The relationship
203. between age-related development of spike-and-wave discharges
204. and the resistance to amygdaloid kindling in rats with genetic
205. absence epilepsy. Neurobiol Dis 2008;32:355–63.
206. Akman O, Gulcebi MI, Carcak N, Ketenci Ozatman S, Eryigit T,
207. Moshé SL, Galanopoulou AS, Yilmaz Onat F. The role of the substantia
208. nigra pars reticulata in kindling resistance in rats with genetic
209. absence epilepsy. Epilepsia 2015; 56:1793–802.
210. Gigout S, Louvel J, Pumain R. Effects in vitro and in vivo of a gap
211. junction blocker on epileptiform activities in a genetic model of
212. absence epilepsy. Epilepsy Res 2006;69:15–29.
213. Moshé SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances.
214. Lancet 2015;385:884–98.