Critical evaluation of P2X7 receptor antagonists in selected seizure models

PLoS ONE

Volumn 11, Issue 6, 2016, Pages

  Fischer, Wolfgang ^a   Franke, Heike ^a   Krügel, Ute ^a   Müller, Heiko ^b   Dinkel, Klaus ^b,c   Lord, Brian ^d   Letavic, Michael A ^d   Henshall, David C ^e   Engel, Tobias ^e  

^a UNIVERSITY OF LEIPZIG   (Germany)

^b Lead Discovery Center GmbH   (Germany)

^c Affectis Pharmaceutical AG   (Germany)

^d JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^e ROYAL COLLEGE OF SURGEONS IN IRELAND   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

AFC 5128; BRILLIANT BLUE G; CARBAMAZEPINE; CHOLINERGIC RECEPTOR BLOCKING AGENT; ETHOSUXIMIDE; GLIAL FIBRILLARY ACIDIC PROTEIN; IBA 1 PROTEIN; MESSENGER RNA; N [[4 (4 PHENYLPIPERAZIN 1 YL)TETRAHYDRO 2H PYRAN 4 YL]METHYL] 2 (PHENYLTHIO)NICOTINAMIDE; PURINERGIC P2X RECEPTOR ANTAGONIST; PURINERGIC P2X7 RECEPTOR; TANSHINONE IIA; UNCLASSIFIED DRUG; VALPROIC ACID; ANTICONVULSIVE AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTICONVULSANT ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG EFFICACY; DRUG POTENCY; DRUG POTENTIATION; DRUG STRUCTURE; ELECTROSHOCK SEIZURE; ELECTROSHOCK-INDUCED CONVULSION; HIPPOCAMPAL CA3 REGION; HUMAN; HUMAN CELL; KINDLING; MALE; MOUSE; NONHUMAN; PENTYLENETETRAZOLE-INDUCED SEIZURE; RAT; SEIZURE; SEIZURE THRESHOLD; TONIC CLONIC SEIZURE; ANIMAL; CHEMICALLY INDUCED; CHEMISTRY; DISEASE MODEL; DOSE RESPONSE; DRUG EFFECTS; ELECTROSHOCK; EPILEPSY; EVALUATION STUDY; GENETICS; METABOLISM; PATHOLOGY; WISTAR RAT;

ANIMALS; ANTICONVULSANTS; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; ELECTROSHOCK; EPILEPSY; KINDLING, NEUROLOGIC; MALE; MICE; PURINERGIC P2X RECEPTOR ANTAGONISTS; RATS; RATS, WISTAR; RECEPTORS, PURINERGIC P2X7; SEIZURES;

EID: 84976320015     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0156468     Document Type: Article

References (104)

1. Baulac M, Pitkänen A (2009) Research priorities in epilepsy for the next decade - A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17-18 January 2008. Epilepsia 50(3): 571-583.
2. Perucca E, Covanis A, Dua T (2014) Commentary: Epilepsy is a Global Problem. Epilepsia 55(9): 1326-1328. doi: 10.1111/epi.12725 PMID: 25092469
3. Moshé SL, Perucca E, Ryvlin P, Tomson T (2015) Epilepsy: new advances. Lancet 385(9971): 884-898. doi: 10.1016/S0140-6736(14)60456-6 PMID: 25260236
4. Löscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 20(5): 359-368. doi: 10.1016/j.seizure. 2011.01.003 PMID: 21292505
5. Löscher W, Klitgaard H, Twyman RE, Schmidt D (2013) New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 12(10): 757-776. doi: 10.1038/nrd4126 PMID: 24052047
6. Xu D, Miller SD, Koh S (2013) Immune mechanisms in epileptogenesis. Front Cell Neurosci 7: 195. doi: 10.3389/fncel.2013.00195 PMID: 24265605
7. Di Maio R (2014) Neuronal mechanisms of epileptogenesis. Front Cell Neurosci 8: 29. doi: 10.3389/fncel.2014.00029 PMID: 24600345
8. Kaminski RM, Rogawski MA, Klitgaard H (2014) The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments. Neurotherapeutics 11(2): 385-400. doi: 10.1007/s13311-014-0266-1 PMID: 24671870
9. Griffin WS (2006) Inflammation and neurodegenerative diseases. Am J Clin Nutr 83(2): 470S-474S. PMID: 16470015
10. Choi J, Koh S (2008) Role of brain inflammation in epileptogenesis. Yonsei Med J 49(1): 1-18. doi: 10.3349/ymj.2008.49.1.1 PMID: 18306464
11. Somera-Molina KC, Nair S, Van Eldik LJ, Watterson DM, Wainwright MS (2009) Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model. Brain Res 1282: 162-172. doi: 10.1016/j.brainres. 2009.05.073 PMID: 19501063
12. Vezzani A (2014) Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Curr 14 (Suppl 1): 3-7.
13. Ravizza T, Gagliardi B, Noé F, Boer K, Aronica E, Vezzani A (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis 29(1): 142-160. PMID: 17931873
14. Aronica E, Crino PB (2011) Inflammation in epilepsy: clinical observations. Epilepsia 52 (Suppl 3): 26-32. doi: 10.1111/j.1528-1167.2011.03033.x PMID: 21542843
15. Maroso M, Balosso S, Ravizza T, Liu J, Bianchi ME, Vezzani A (2011) Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1β and high-mobility group box 1. J Intern Med 270(4): 319-326. doi: 10.1111/j.1365-2796.2011.02431.x PMID: 21793950
16. A currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol Dis 82: 311-320. doi: 10.1016/j.nbd.2015.07.003 PMID: 26168875
17. Uludag IF, Duksal T, Tiftikcioglu BI, Zorlu Y, Ozkaya F, Kirkali G (2015) IL-1β, IL-6 and IL1Ra levels in temporal lobe epilepsy. Seizure 26: 22-25. doi: 10.1016/j.seizure.2015.01.009 PMID: 25799897
18. Vezzani A (2015) Anti-inflammatory drugs in epilepsy: does it impact epileptogenesis? Expert Opin Drug Saf 14(4): 583-592. doi: 10.1517/14740338.2015.1010508 PMID: 25645535
19. Engel T, Jimenez-Pacheco A, Miras-Portugal MT, Diaz-Hernandez M, Henshall DC (2012) P2X7 receptor in epilepsy; role in pathophysiology and potential targeting for seizure control. Int J Physiol Pathophysiol Pharmacol 4(4): 174-187. PMID: 23320131
20. Henshall DC, Diaz-Hernandez M, Miras-Portugal MT, Engel T (2013) P2X receptors as targets for the treatment of status epilepticus. Front Cell Neurosci 7: 237. doi: 10.3389/fncel.2013.00237 PMID: 24324404
21. Engel T, Alves M, Sheedy C, Henshall DC (2015) ATPergic signalling during seizures and epilepsy. Neuropharmacology pii: S0028-3908(15)30165-9. doi: 10.1016/j.neuropharm.2015.11.001 [Epub ahead of print].
22. 7 receptor as a therapeutic target. Expert Opin Ther Targets 12(5): 647-661. doi: 10.1517/14728222. 12.5.647 PMID: 18410246
23. Volonté C, Apolloni S, Skaper SD, Burnstock G (2012) P2X7 receptors: channels, pores and more. CNS Neurol Disord Drug Targets 11(6): 705-721. PMID: 22963440
24. Jiang LH, Baldwin JM, Roger S, Baldwin SA (2013) Insights into the molecular mechanisms underlying mammalian P2X7 receptor functions and contributions in diseases, revealed by structural modeling and single nucleotide polymorphisms. Front Pharmacol 4: 55. doi: 10.3389/fphar.2013.00055 PMID: 23675347
25. Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G (1997) Tissue distribution of the P2X7 receptor. Neuropharmacology 36(9): 1277-1283. PMID: 9364482
26. Sim JA, Young MT, Sung HY, North RA, Surprenant A (2004) Reanalysis of P2X7 receptor expression in rodent brain. J Neurosci 24(28):6307-6314. PMID: 15254086
27. Sperlágh B, Vizi ES, Wirkner K, Illes P (2006) P2X7 receptors in the nervous system. Prog Neurobiol 78(6): 327-346. PMID: 16697102
28. Marín-García P, Sánchez-Nogueiro J, Gómez-Villafuertes R, León D, Miras-Portugal MT (2008) Synaptic terminals from mice midbrain exhibit functional P2X7 receptor. Neuroscience 151(2): 361-373. PMID: 18082965
29. Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, et al. (2006) The P2X7 receptor: a key player in IL-1 processing and release. J Immunol. 176(7): 3877-3883.
30. Erratum Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, et al. The P2X7 receptor: a key player in IL-1 processing and release in: J Immunol 179 (12): 8569 (2007). PMID: 16547218
31. Lister MF, Sharkey J, Sawatzky DA, Hodgkiss JP, Davidson DJ, Rossi AG, et al. (2007) The role of the purinergic P2X7 receptor in inflammation. J Inflamm (Lond) 4: 5.
32. Di Virgilio F (2015) P2X receptors and inflammation. Curr Med Chem 22(7): 866-877. PMID: 25524252
33. Sperlágh B, Illes P (2014) P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci 35(10): 537-547. doi: 10.1016/j.tips.2014.08.002 PMID: 25223574
34. 7 receptor-pannexin connection to dye uptake and IL-1β release. Purinergic Signal 5(2): 129-137. doi: 10.1007/s11302-009-9141-7 PMID: 19212823
35. Coddou C, Yan Z, Obsil T, Huidobro-Toro JP, Stojilkovic SS (2011) Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev 63(3): 641-683. doi: 10.1124/pr.110.003129 PMID: 21737531
36. 7 receptors. J Biol Chem 276(1): 125-132. PMID: 11016935
37. Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, et al. (2002) Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol 168 (12): 6436-6445. PMID: 12055263
38. 7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114(3): 386-396. PMID: 15777864
39. 7 purinergic receptor: from physiology to neuronal disorders. FASEB J 24(2): 337-345. doi: 10.1096/fj.09-138883 PMID: 19812374
40. Ravizza T, Balosso S, Vezzani A (2011) Inflammation and prevention of epileptogenesis. Neurosci Lett 497(3): 223-230. doi: 10.1016/j.neulet.2011.02.040 PMID: 21362451
41. Hunt RF, Boychuk JA, Smith BN (2013) Neural circuit mechanisms of post-traumatic epilepsy. Front Cell Neurosci 7: 89. doi: 10.3389/fncel.2013.00089 PMID: 23785313
42. Arbeloa J, Pérez-Samartín A, Gottlieb M, Matute C (2012) P2X7 receptor blockade prevents ATP excitotoxicity in neurons and reduces brain damage after ischemia. Neurobiol Dis 45(3): 954-961. doi: 10.1016/j.nbd.2011.12.014 PMID: 22186422
43. Franke H, Illes P (2014) Pathological potential of astroglial purinergic receptors. Adv Neurobiol 11: 213-256. doi: 10.1007/978-3-319-08894-5-11 PMID: 25236731
44. Rodrigues RJ, Tomé AR, Cunha RA (2015) ATP as a multi-target danger signal in the brain. Front Neurosci 9: 148. doi: 10.3389/fnins.2015.00148 PMID: 25972780
45. Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, et al. (2002) Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia 43 (Suppl 5): 30-35. PMID: 12121291
46. Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, et al. (2011) Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 8(2): 304-315. doi: 10.1007/s13311-011-0039-z PMID: 21431948
47. Vianna EP, Ferreira AT, Naffah-Mazzacoratti MG, Sanabria ER, Funke M, Cavalheiro EA, et al. (2002) Evidence that ATP participates in the pathophysiology of pilocarpine-induced temporal lobe epilepsy: fluorimetric, immunohistochemical, and Western blot studies. Epilepsia 43 (Suppl 5): 227-229. PMID: 12121326
48. Doná F, Ulrich H, Persike DS, Conceição IM, Blini JP, Cavalheiro EA, et al. (2009) Alteration of purinergic P2X4 and P2X7 receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine. Epilepsy Res 83(2-3): 157-167. doi: 10.1016/j.eplepsyres.2008.10.008 PMID: 19084381
49. Rappold PM, Lynd-Balta E, Joseph SA (2006) P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain. Brain Res 1089(1): 171-178. PMID: 16635480
50. Da Silva Fernandes MJ, Da Graça Naffah Mazzacoratti M, Cavalheiro EA (2010) Pathophysiological Aspects of Temporal Lobe Epilepsy and the Role of P2X Receptors. Open Neurosci J 4, 35-43.
51. Engel T, Gomez-Villafuertes R, Tanaka K, Mesuret G, Sanz-Rodriguez A, Garcia-Huerta P, et al. (2012) Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice. FASEB J 26(4): 1616-1628. doi: 10.1096/fj.11-196089 PMID: 22198387
52. Jimenez-Pacheco A, Mesuret G, Sanz-Rodriguez A, Tanaka K, Mooney C, Conroy R, et al. (2013) Increased neocortical expression of the P2X7 receptor after status epilepticus and anticonvulsant effect of P2X7 receptor antagonist A-438079. Epilepsia 54(9): 1551-1561. doi: 10.1111/epi.12257 PMID: 23808395
53. Padrão RA, Ariza CB, Canzian M, Porcionatto M, Araújo MGL, Cavalheiro EA, et al. (2011) The P2 purinergic receptors are increased in the hippocampus of patients with temporal lobe epilepsy: what is the relevance to the epileptogenesis? Purinergic Signal 7:127.
54. Barros-Barbosa AR, Fonseca AL, Guerra-Gomes S, Ferreirinha F, Santos A, Rangel R et al. (2016) Up-regulation of P2X7 receptor-mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex. Epilepsia 57(1): 99-110. doi: 10.1111/epi.13263 PMID: 26714441
55. Bartlett R, Stokes L, Sluyter R (2014) The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol Rev 66(3): 638-675. doi: 10.1124/pr.113.008003 PMID: 24928329
56. Chrovian CC, Rech JC, Bhattacharya A, Letavic MA (2014) P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders. Prog Med Chem 53: 65-100. doi: 10.1016/B978-0-444-63380-4.00002-0 PMID: 24418608
57. Amhaoul H, Ali I, Mola M, Van Eetveldt A, Szewczyk K, Missault S, Bielen K et al. (2016) P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy. Neuropharmacology 105: 175-185. doi: 10.1016/j.neuropharm.2016.01.018 PMID: 26775823
58. Kim JE, Kang TC (2011) The P2X7 receptor-pannexin-1 complex decreases muscarinic acetylcholine receptor-mediated seizure susceptibility in mice. J Clin Invest 121(5): 2037-2047. doi: 10.1172/JCI44818 PMID: 21505260
59. 7 receptors. Mol Pharmacol 58(1): 82-88. PMID: 10860929
60. Bhattacharya A, Wang Q, Ao H, Shoblock JR, Lord B, Aluisio L, et al. (2013) Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567. Br J Pharmacol 170(3): 624-640. doi: 10.1111/bph.12314 PMID: 23889535
61. Bös M (2009) Inventor; Affectis Pharmaceuticals AG, assignee. Novel PX7 antagonists and their use. Patent WO 2009118175A1.
62. Kaiser M, Sobottka H, Fischer W, Schaefer M, Nörenberg W (2014) Tanshinone II A sulfonate, but not tanshinone II A, acts as potent negative allosteric modulator of the human purinergic receptor P2X7. J Pharmacol Exp Ther 350(3): 531-542. doi: 10.1124/jpet.114.214569 PMID: 24970925
63. Löscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52(4): 657-678. doi: 10.1111/j.1528-1167.2011.03024.x PMID: 21426333
64. Yuen ESM, Trocóniz IF (2015) Can pentylenetetrazole and maximal electroshock rodent seizure models quantitatively predict antiepileptic efficacy in humans? Seizure 24: 21-27. doi: 10.1016/j.seizure.2014.11.006 PMID: 25564315
65. Fischer W, Kittner H (1998) Influence of ethanol on the pentylenetetrazol-induced kindling in rats. J Neural Transm 105(10-12): 1129-1142. PMID: 9928883
66. Dhir A (2012) Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci Chapter 9: Unit9.37 doi: 10.1002/0471142301.ns0937s58 PMID: 23042503
67. Chen Z, Li WD, Zhu LJ, Shen YJ, Wei EQ (2002) Effects of histidine, a precursor of histamine, on pentylenetetrazole-induced seizures in rats. Acta Pharmacol Sin 23(4): 361-366. PMID: 11931695
68. th Joint German-Italian Purine Club Meeting. International Conference on Purinergic Signalling. Hamburg, July 23-25, 2015. Ref. in: Abstract Handbook, Universität Hamburg, P. 85-86.
69. Fischer W, Urban N, Immig K, Franke H, Schaefer M (2014) Natural compounds with P2X7 receptormodulating properties. Purinergic Signal 10(2): 313-326. doi: 10.1007/s11302-013-9392-1 PMID: 24163006
70. Fischer W (2002) Anticonvulsant profile and mechanism of action of propranolol and its two enantiomers. Seizure 11(5): 285-302. PMID: 12076101
71. Ramanjaneyulu R, Ticku MK (1984) Interactions of pentamethylenetetrazole and tetrazole analogues with the picrotoxinin site of the benzodiazepine-GABA receptor-ionophore complex. Eur J Pharmacol 98(3-4): 337-345. PMID: 6327331
72. 3H] JNJ-54232334. Eur J Pharmacol 765: 551-559. doi: 10. 1016/j.ejphar.2015.09.026 PMID: 26386289
73. Jimenez-Mateos EM, Engel T, Merino-Serrais P, McKiernan RC, Tanaka K, Mouri G, et al. (2012) Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med 18(7): 1087-1094. doi: 10.1038/nm.2834 PMID: 22683779
74. Franke H, Kittner H (2001) Morphological alterations of neurons and astrocytes and changes in emotional behavior in pentylenetetrazol-kindled rats. Pharmacol Biochem Behav 70(2-3): 291-303. PMID: 11701200
75. Suttkus A, Rohn S, Jäger C, Arendt T, Morawski M (2012) Neuroprotection against iron-induced cell death by perineuronal nets - an in vivo analysis of oxidative stress. Am J Neurodegener Dis 1(2): 122-129. PMID: 23383386
76. Franke H, Günther A, Grosche J, Schmidt R, Rossner S, Reinhardt R, et al. (2004) P2X7 receptor expression after ischemia in the cerebral cortex of rats. J Neuropathol Exp Neurol 63(7): 686-699. PMID: 15290894
77. 7 receptor is neuroprotective in an animal model of Alzheimer's disease. Neuroreport 19(17): 1715-1719. doi: 10.1097/WNR.0b013e3283179333 PMID: 18852683
78. Kimbler DE, Shields J, Yanasak N, Vender JR, Dhandapani KM (2012) Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice. PLoS One 7(7): e41229. doi: 10.1371/journal.pone.0041229 PMID: 22815977
79. Lam BYH, Lo ACY, Sun X, Luo HW, Chung SK, Sucher NJ (2003) Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice. Phytomedicine 10(4): 286-291. PMID: 12809358
80. Yin X, Yin Y, Cao FL, Chen YF, Peng Y, Hou WG, et al. (2012) Tanshinone IIA attenuates the inflammatory response and apoptosis after traumatic injury of the spinal cord in adult rats. PLoS One 7(6): e38381. doi: 10.1371/journal.pone.0038381 PMID: 22675554
81. Letavic MA, Lord B, Bischoff F, Hawryluk NA, Pieters S, Rech JC, et al. (2013) Synthesis and pharmacological characterization of two novel, brain penetrating P2X7 antagonists. ACS Med Chem Lett 4 (4): 419-422. doi: 10.1021/ml400040v PMID: 24900687
82. Rogawski MA, Löscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5(7): 553-564. PMID: 15208697
83. Mesuret G, Engel T, Hessel EV, Sanz-Rodriguez A, Jimenez-Pacheco A, Miras-Portugal MT, et al. (2014) P2X7 receptor inhibition interrupts the progression of seizures in immature rats and reduces hippocampal damage. CNS Neurosci Ther 20(6): 556-564. doi: 10.1111/cns.12272 PMID: 24750893
84. Mouri G, Jimenez-Mateos E, Engel T, Dunleavy M, Hatazaki S, Paucard A, et al. (2008) Unilateral hippocampal CA3-predominant damage and short latency epileptogenesis after intra-amygdala microinjection of kainic acid in mice. Brain Res 1213: 140-151. doi: 10.1016/j.brainres.2008.03.061 PMID: 18455706
85. Ono J, Vieth RF, Walson PD (1990) Electrocorticographical observation of seizures induced by pentylenetetrazol (PTZ) injection in rats. Funct Neurol 5(4): 345-352. PMID: 2093053
86. Corda MG, Orlandi M, Lecca D, Giorgi O (1992) Decrease in GABAergic function induced by pentylenetetrazol kindling in rats: antagonism by MK-801. J Pharmacol Exp Ther 262(2): 792-800. PMID: 1323663
87. Soni N, Koushal P, Reddy BV, Deshmukh R, Kumar P (2015) Effect of GLT-1 modulator and P2X7 antagonists alone and in combination in the kindling model of epilepsy in rats. Epilepsy Behav 48: 4-14. doi: 10.1016/j.yebeh.2015.04.056 PMID: 26037843
88. Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, et al. (2008) Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest 118(2): 571-582. doi: 10.1172/JCI33737 PMID: 18172552
89. Cherubini E, Miles R (2015) The CA3 region of the hippocampus: how is it? What is it for? How does it do it? Front Cell Neurosci 9: 19. doi: 10.3389/fncel.2015.00019 PMID: 25698930
90. Avignone E, Ulmann L, Levavasseur F, Rassendren F, Audinat E (2008) Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci 28 (37): 9133-9144. doi: 10.1523/JNEUROSCI.1820-08.2008 PMID: 18784294
91. Choi HK, Ryu HJ, Kim JE, Jo SM, Choi HC, Song HK, et al. (2012) The roles of P2X7 receptor in regional-specific microglial responses in the rat brain following status epilepticus. Neurol Sci 33 (3):515-525. doi: 10.1007/s10072-011-0740-z PMID: 21845474
92. Kraft AD, McPherson CA, Harry GJ (2009) Heterogeneity of microglia and TNF signaling as determinants for neuronal death or survival. Neurotoxicology 30(5): 785-793. doi: 10.1016/j.neuro.2009.07.001 PMID: 19596372
93. Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339(6116): 156-161. doi: 10.1126/science.1227901 PMID: 23307732
94. Lourbopoulos A, Ertürk A, Hellal F (2015) Microglia in action: how aging and injury can change the brain's guardians. Front Cell Neurosci 9: 54. doi: 10.3389/fncel.2015.00054 PMID: 25755635
95. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1): 7-35. doi: 10.1007/s00401-009-0619-8 PMID: 20012068
96. Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, Rempe D, Rodríguez JJ, et al. (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4(3): art:e00082.
97. Robel S, Buckingham SC, Boni JL, Campbell SL, Danbolt NC, Riedemann T, et al. (2015) Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci 35(8): 3330-3345. doi: 10.1523/JNEUROSCI.1574-14.2015 PMID: 25716834
98. Steinhäuser C, Seifert G (2012) Astrocyte dysfunction in epilepsy. In:Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds). Jasper's Basic Mechanisms of the Epilepsies [Internet], 4th edn. Bethesda (MD): National Center for Biotechnology Information (US), pp1-15.
99. Bedner P, Dupper A, Hüttmann K, Müller J, Herde MK, Dublin P, et al. (2015) Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138(Pt 5): 1208-1222. doi: 10.1093/brain/awv067 PMID: 25765328
100. Wee Yong V (2010) Inflammation in neurological disorders: a help or a hindrance? Neuroscientist 16 (4): 408-420. doi: 10.1177/1073858410371379 PMID: 20817918
101. Kim JE, Kwak SE, Jo SM, Kang TC (2009 Blockade of P2X receptor prevents astroglial death in the dentate gyrus following pilocarpine-induced status epilepticus. Neurol Res 31(9): 982-988. doi: 10. 1179/174313209X389811 PMID: 19138473
102. Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, et al. (2013) Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 59: 183-193. doi: 10.1016/j.nbd.2013.07.015 PMID: 23938763
103. McNamara JO, Huang YZ, Leonard AS (2006) Molecular signaling mechanisms underlying epileptogenesis. Sci STKE 356: re12.
104. 7 receptors: properties and relevance to CNS function. Glia 54(7): 738-746. PMID: 17006902