Novel frontiers in epilepsy treatments: Preventing epileptogenesis by targeting inflammation

Expert Review of Neurotherapeutics

Volumn 13, Issue 6, 2013, Pages 615-625

  D'Ambrosio, Raimondo ^a,b   Eastman, Clifford L ^a   Fattore, Cinzia ^c   Perucca, Emilio ^c  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

^c UNIVERSITY OF PAVIA   (Italy)

Author keywords

clinical trials; disease modification; drug treatment; epilepsy; epileptogenesis; experimental models; hypothermia; inflammation; traumatic brain injury

Indexed keywords

3 HYDROXY 3 METHYLGLUTARYL COENZYME A; ACETYLSALICYLIC ACID; ANTICONVULSIVE AGENT; ATORVASTATIN; CARBAMAZEPINE; CARISBAMATE; CELECOXIB; CYCLOOXYGENASE 2 INHIBITOR; ERYTHROPOIETIN; ETHOSUXIMIDE; INDOMETACIN; MEVINOLIN; MINOCYCLINE; MONTELUKAST; NIMESULIDE; PARECOXIB; PRAVASTATIN; PROGESTERONE; RAPAMYCIN; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; ROSUVASTATIN; SIMVASTATIN; THALIDOMIDE; VALPROIC ACID;

ANTICONVULSANT THERAPY; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; ARTICLE; BLOOD BRAIN BARRIER; CEREBROVASCULAR ACCIDENT; DISEASE DURATION; DRUG SAFETY; DRUG TARGETING; DRUG TREATMENT FAILURE; EARLY INTERVENTION; ENCEPHALITIS; EPILEPSY; EPILEPTIC FOCUS; EPILEPTIC STATE; EPILEPTOGENESIS; EXPERIMENTAL THERAPY; FOCAL EPILEPSY; FOLLOW UP; HIGH FREQUENCY OSCILLATION; HUMAN; INDUCED HYPOTHERMIA; MAGNETOENCEPHALOGRAPHY; MORTALITY; NEUROPROTECTION; NONHUMAN; PROPHYLAXIS; RISK FACTOR; TRAUMATIC BRAIN INJURY; TRAUMATIC EPILEPSY; TREATMENT DURATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTICONVULSANTS; EPILEPSY; HUMANS; HYPOTHERMIA, INDUCED; INFLAMMATION;

EID: 84879099094     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.13.54     Document Type: Article

References (165)

1. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 78(20), 1548-1554 (2012).
2. Loscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52(4), 657-678 (2011).
3. Herman ST. Clinical trials for prevention of epileptogenesis. Epilepsy Res. 68(1), 35-38 (2006). (Pubitemid 43052776)
4. Beghi E. Overview of studies to prevent posttraumatic epilepsy. Epilepsia 44(Suppl. 10), 21-26 (2003). (Pubitemid 37280389)
5. Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 42(4), 515-524 (2001). (Pubitemid 32322197)
6. Temkin NR. Preventing and treating posttraumatic seizures: the human experience. Epilepsia 50(Suppl. 2), 10-13 (2009).
7. Mani R, Pollard J, Dichter MA. Human clinical trails in antiepileptogenesis. Neurosci. Lett. 497(3), 251-256 (2011).
8. Galanopoulou AS, Buckmaster PS, Staley KJ et al.; American Epilepsy Society Basic Science Committee And The International League Against Epilepsy Working Group On Recommendations For Preclinical Epilepsy Drug Discovery. Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 53(3), 571-582 (2012).
9. Schmidt D. Is antiepileptogenesis a realistic goal in clinical trials? Concerns and new horizons. Epileptic Disord. 14(2), 105-113 (2012).
10. Loscher W, Brandt C. Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol. Rev. 62(4), 668-700 (2010).
11. Pitkanen A, Bolkvadze T, Immonen R. Anti-epileptogenesis in rodent post-traumatic epilepsy models. Neurosci. Lett. 497(3), 163-171 (2011).
12. Sloviter RS. Progress on the issue of excitotoxic injury modification vs. real neuroprotection; implications for posttraumatic epilepsy. Neuropharmacology 61(5-6), 1048-1050 (2011).
13. D'Ambrosio R, Fairbanks JP, Fender JS, Born DE, Doyle DL, Miller JW. Post-traumatic epilepsy following fluid percussion injury in the rat. Brain 127(Pt 2), 304-314 (2004). (Pubitemid 38160315)
14. D'Ambrosio R, Fender JS, Fairbanks JP et al. Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat. Brain 128(Pt 1), 174-188 (2005). (Pubitemid 40070531)
15. Hunt RF, Scheff SW, Smith BN. Posttraumatic epilepsy after controlled cortical impact injury in mice. Exp. Neurol. 215(2), 243-252 (2009).
16. Dube C, Richichi C, Bender RA, Chung G, Litt B, Baram TZ. Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis. Brain 129(Pt 4), 911-922 (2006).
17. Oakley JC, Kalume F, Yu FH, Scheuer T, Catterall WA. Temperature-and agedependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proc. Natl Acad. Sci. USA 106(10), 3994-3999 (2009).
18. Buckingham SC, Campbell SL, Haas BR et al. Glutamate release by primary brain tumors induces epileptic activity. Nat. Med. 17(10), 1269-1274 (2011).
19. Williams PA, Dudek FE. A chronic histopathological and electrophysiological analysis of a rodent hypoxic-ischemic brain injury model and its use as a model of epilepsy. Neuroscience 149(4), 943-961 (2007). (Pubitemid 350122888)
20. Rakhade SN, Klein PM, Huynh T et al. Development of later life spontaneous seizures in a rodent model of hypoxiainduced neonatal seizures. Epilepsia 52(4), 753-765 (2011).
21. Kelly KM, Kharlamov A, Hentosz TM et al. Photothrombotic brain infarction results in seizure activity in aging Fischer 344 and Sprague Dawley rats. Epilepsy Res. 47(3), 189-203 (2001). (Pubitemid 34008463)
22. Kharlamov EA, Jukkola PI, Schmitt KL, Kelly KM. Electrobehavioral characteristics of epileptic rats following photothrombotic brain infarction. Epilepsy Res. 56(2-3), 185-203 (2003). (Pubitemid 37464931)
23. Stewart KA, Wilcox KS, Fujinami RS, White HS. Development of postinfection epilepsy after Theiler's virus infection of C57BL/6 mice. J. Neuropathol. Exp. Neurol. 69(12), 1210-1219 (2010).
24. Agrawal A, Timothy J, Pandit L, Manju M. Post-traumatic epilepsy: an overview. Clin. Neurol. Neurosurg. 108(5), 433-439 (2006).
25. Eftekhar B, Sahraian MA, Nouralishahi B et al. Prognostic factors in the persistence of posttraumatic epilepsy after penetrating head injuries sustained in war. J. Neurosurg. 110(2), 319-326 (2009).
26. Christensen J. Traumatic brain injury: risks of epilepsy and implications for medicolegal assessment. Epilepsia 53(Suppl. 4), 43-47 (2012).
27. Frey LC. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia 44(Suppl. 10), 11-17 (2003). (Pubitemid 37280387)
28. Eastman CL, Verley DR, Fender JS, Temkin NR, D'Ambrosio R. ECoG studies of valproate, carbamazepine and halothane in frontal-lobe epilepsy induced by head injury in the rat. Exp. Neurol. 224(2), 369-388 (2010).
29. Eastman CL, Verley DR, Fender JS et al. Antiepileptic and antiepileptogenic performance of carisbamate after head injury in the rat: blind and randomized studies. J. Pharmacol. Exp. Ther. 336(3), 779-790 (2011).
30. Thompson HJ, Lifshitz J, Marklund N et al. Lateral fluid percussion brain injury: a 15-year review and evaluation. J. Neurotrauma 22(1), 42-75 (2005).
31. D'Ambrosio R, Eastman CL, Darvas F et al. Mild passive focal cooling prevents epileptic seizures after head injury in rats. Ann. Neurol. 73(2), 199-209 (2013).
32. Curia G, Levitt M, Fender JS, Miller JW, Ojemann J, D'Ambrosio R. Impact of injury location and severity on posttraumatic epilepsy in the rat: role of frontal neocortex. Cereb. Cortex 21(7), 1574-1592 (2011).
33. Diaz-Arrastia R, Agostini MA, Madden CJ, Van Ness PC. Posttraumatic epilepsy: the endophenotypes of a human model of epileptogenesis. Epilepsia 50(Suppl. 2), 14-20 (2009).
34. Bancaud J, Talairach J. Clinical semiology of frontal lobe seizures. Adv. Neurol. 57, 3-58 (1992).
35. Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. Complex partial seizures of frontal lobe origin. Ann. Neurol. 18(4), 497-504 (1985). (Pubitemid 16138023)
36. Williamson PD, Spencer SS. Clinical and EEG features of complex partial seizures of extratemporal origin. Epilepsia 27(Suppl. 2), S46-S63 (1986). (Pubitemid 16050510)
37. Ikeda A, Hirasawa K, Kinoshita M et al. Negative motor seizure arising from the negative motor area: is it ictal apraxia? Epilepsia 50(9), 2072-2084 (2009).
38. Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. Complex partial seizures of frontal lobe origin. Ann. Neurol. 18(4), 497-504 (1985). (Pubitemid 16138023)
39. Williamson PD, Spencer SS. Clinical and EEG features of complex partial seizures of extratemporal origin. Epilepsia 27(Suppl. 2), S46-S63 (1986). (Pubitemid 16050510)
40. Fox JL, Vu EN, Doyle-Waters M, Brubacher JR, Abu-Laban R, Hu Z. Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review. CJEM 12(4), 355-364 (2010).
41. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 371(9628), 1955-1969 (2008). (Pubitemid 351780491)
42. Jiang JY, Xu W, Li WP et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J. Cereb. Blood Flow Metab. 26(6), 771-776 (2006).
43. Sadaka F, Veremakis C. Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review. Brain Inj. 26(7-8), 899-908 (2012).
44. Liu WG, Qiu WS, Zhang Y, Wang WM, Lu F, Yang XF. Effects of selective brain cooling in patients with severe traumatic brain injury: a preliminary study. J. Int. Med. Res. 34(1), 58-64 (2006).
45. Qiu W, Shen H, Zhang Y et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J. Clin. Neurosci. 13(10), 995-1000 (2006). (Pubitemid 44781193)
46. Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia 52(Suppl. 3), 26-32 (2011).
47. Ravizza T, Balosso S, Vezzani A. Inflammation and prevention of epileptogenesis. Neurosci. Lett. 497(3), 223-230 (2011).
48. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7(1), 31-40 (2011).
49. Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology 69, 16-24 (2013).
50. Xue M, Del Bigio MR. Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci. Lett. 283(3), 230-232 (2000). (Pubitemid 30168975)
51. Katsuki H. Exploring neuroprotective drug therapies for intracerebral hemorrhage. J. Pharmacol. Sci. 114(4), 366-378 (2010).
52. Andersson U, Rauvala H. Introduction: HMGB1 in inflammation and innate immunity. J. Intern. Med. 270(4), 296-300 (2011).
53. Gao TL, Yuan XT, Yang D et al. Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. J. Trauma Acute Care Surg. 72(3), 643-649 (2012).
54. Brown KL, Cosseau C, Gardy JL, Hancock RE. Complexities of targeting innate immunity to treat infection. Trends Immunol. 28(6), 260-266 (2007). (Pubitemid 46824085)
55. Griffiths MR, Gasque P, Neal JW. The regulation of the CNS innate immune response is vital for the restoration of tissue homeostasis (repair) after acute brain injury: a brief review. Int. J. Inflam. 2010, 151097 (2010).
56. Merrill JE, Benveniste EN. Cytokines in inflammatory brain lesions: helpful and harmful. Trends Neurosci. 19(8), 331-338 (1996). (Pubitemid 26349062)
57. Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr. Opin. Crit. Care 8(2), 101-105 (2002). (Pubitemid 36132681)
58. Serhan CN, Brain SD, Buckley CD et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 21(2), 325-332 (2007). (Pubitemid 46213480)
59. Moseley JI, Ojemann GA, Ward AA Jr. Unit activity during focal cortical hypothermia in the normal cortex. Exp. Neurol. 37(1), 152-163 (1972).
60. Fritz HG, Bauer R. Secondary injuries in brain trauma: effects of hypothermia. J. Neurosurg. Anesthesiol. 16(1), 43-52 (2004). (Pubitemid 38057398)
61. Zhao H, Steinberg GK, Sapolsky RM. General versus specific actions of mildmoderate hypothermia in attenuating cerebral ischemic damage. J. Cereb. Blood Flow Metab. 27(12), 1879-1894 (2007). (Pubitemid 350129166)
62. Sahuquillo J, Vilalta A. Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. Curr. Pharm. Des. 13(22), 2310-2322 (2007). (Pubitemid 47317037)
63. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit. Care Med. 37(Suppl. 7), S186-S202 (2009).
64. Dietrich WD, Atkins CM, Bramlett HM. Protection in animal models of brain and spinal cord injury with mild to moderate hypothermia. J. Neurotrauma 26(3), 301-312 (2009).
65. Dietrich WD, Bramlett HM. The evidence for hypothermia as a neuroprotectant in traumatic brain injury. Neurotherapeutics 7(1), 43-50 (2010).
66. Ravizza T, Balosso S, Vezzani A. Inflammation and prevention of epileptogenesis. Neurosci. Lett. 497(3), 223-230 (2011).
67. Librizzi L, Noe F, Vezzani A, de Curtis M, Ravizza T. Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann. Neurol. 72(1), 82-90 (2012).
68. Bartfai T, Sanchez-Alavez M, Andell-Jonsson S et al. Interleukin-1 system in CNS stress: seizures, fever, and neurotrauma. Ann. NY Acad. Sci. 1113, 173-177 (2007). (Pubitemid 350015019)
69. Cederberg D, Siesjo P. What has inflammation to do with traumatic brain injury? Childs. Nerv. Syst. 26(2), 221-226 (2010).
70. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 36(3), 174-184 (2013).
71. Folkersma H, Boellaard R, Yaqub M et al. Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury. J. Nucl. Med. 52(8), 1235-1239 (2011).
72. Ramlackhansingh AF, Brooks DJ, Greenwood RJ et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann. Neurol. 70(3), 374-383 (2011).
73. Cavalli A, Bolognesi ML, Minarini A et al. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 51(3), 347-372 (2008). (Pubitemid 351252260)
74. Mencher SK, Wang LG. Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC Clin. Pharmacol. 5(1), 3 (2005).
75. Margulies S, Hicks R; Combination therapies for traumatic brain injury workshop leaders. Combination therapies for traumatic brain injury: prospective considerations. J. Neurotrauma 26(6), 925-939 (2009).
76. Vink R, Nimmo AJ. Multifunctional drugs for head injury. Neurotherapeutics 6(1), 28-42 (2009).
77. Lampl Y, Boaz M, Gilad R et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69(14), 1404-1410 (2007). (Pubitemid 47511461)
78. Stein DG. Is progesterone a worthy candidate as a novel therapy for traumatic brain injury? Dialogues Clin. Neurosci. 13(3), 352-359 (2011).
79. Ma J, Huang S, Qin S, You C. Progesterone for acute traumatic brain injury. Cochrane Database Syst. Rev. 10, CD008409 (2012).
80. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol. 3(12), 744-751 (2004). (Pubitemid 39535260)
81. Jordan J, Fernandez-Gomez FJ, Ramos M, Ikuta I, Aguirre N, Galindo MF. Minocycline and cytoprotection: shedding new light on a shadowy controversy. Curr. Drug Deliv. 4(3), 225-231 (2007). (Pubitemid 47025406)
82. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 48(6), 1393-1399; discussion 1399 (2001).
83. Siopi E, Llufriu-Daben G, Fanucchi F, Plotkine M, Marchand-Leroux C, Jafarian-Tehrani M. Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: the effect of minocycline. Neurosci. Lett. 511(2), 110-115 (2012).
84. Wang DD, Englot DJ, Garcia PA, Lawton MT, Young WL. Minocycline-and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav. 24(3), 314-318 (2012).
85. Heo K, Cho YJ, Cho KJ et al. Minocycline inhibits caspase-dependent and-independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. Neurosci. Lett. 398(3), 195-200 (2006). (Pubitemid 43673696)
86. Lu DC, Zador Z, Yao J, Fazlollahi F, Manley GT. Aquaporin-4 reduces post-traumatic seizure susceptibility by promoting astrocytic glial scar formation in mice. J. Neurotrauma doi:10.1089/neu.2011.2114 (2011) (Epub ahead of print).
87. Abraham J, Fox PD, Condello C, Bartolini A, Koh S. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol. Dis. 46(2), 425-430 (2012).
88. Nowak M, Strzelczyk A, Reif PS et al. Minocycline as potent anticonvulsant in a patient with astrocytoma and drug resistant epilepsy. Seizure 21(3), 227-228 (2012).
89. Hua F, Wang J, Ishrat T et al. Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. J. Neuroinflammation 8, 42 (2011).
90. Jiang C, Wang J, Li X, Liu C, Chen N, Hao Y. Progesterone exerts neuroprotective effects by inhibiting inflammatory response after stroke. Inflamm. Res. 58(9), 619-624 (2009).
91. Luoma JI, Kelley BG, Mermelstein PG. Progesterone inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity. Steroids 76(9), 845-855 (2011).
92. Siopi E, Cho AH, Homsi S et al. Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update. Neuroscience. 191, 101-106 (2011).
93. Stein DG, Sayeed I. Is progesterone worth consideration as a treatment for brain injury? AJR. Am. J. Roentgenol. 194(1), 20-22 (2010).
94. Espinoza TR, Wright DW. The role of progesterone in traumatic brain injury. J. Head Trauma Rehabil. 26(6), 497-499 (2011).
95. Singh M, Su C. Progesterone, brain-derived neurotrophic factor and neuroprotection. Neuroscience 239, 84-91 (2012).
96. Gibson CL, Gray LJ, Bath PM, Murphy SP. Progesterone for the treatment of experimental brain injury; a systematic review. Brain 131(Pt 2), 318-328 (2008). (Pubitemid 351197603)
97. Sayeed I, Stein DG. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog. Brain Res. 175, 219-237 (2009).
98. Wright DW, Kellermann AL, Hertzberg VS et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann. Emerg. Med. 49(4), 391-402, 402.e1 (2007).
99. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit. Care 12(2), R61 (2008).
100. Raymont V, Salazar AM, Lipsky R, Goldman D, Tasick G, Grafman J. Correlates of posttraumatic epilepsy 35 years following combat brain injury. Neurology 75(3), 224-229 (2010).
101. Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N. Engl. J. Med. 338(1), 20-24 (1998). (Pubitemid 28040171)
102. Ryvlin P, Montavont A, Nighoghossian N. Optimizing therapy of seizures in stroke patients. Neurology 67(12 Suppl. 4), S3-S9 (2006). (Pubitemid 44967989)
103. Jennett B. Outcome after severe head injury: definitions and predictions. Med. J. Aust. 2(13), 475-477 (1976).
104. Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia 44(Suppl. 10), 18-20 (2003). (Pubitemid 37280388)
105. D'Ambrosio R, Hakimian S, Stewart T et al. Functional definition of seizure provides new insight into post-traumatic epileptogenesis. Brain 132(Pt 10), 2805-2821 (2009).
106. Stead M, Bower M, Brinkmann BH et al. Microseizures and the spatiotemporal scales of human partial epilepsy. Brain 133(9), 2789-2797 (2010).
107. Devinsky O, Kelley K, Porter RJ, Theodore WH. Clinical and electroencephalographic features of simple partial seizures. Neurology 38(9), 1347-1352 (1988).
108. Devinsky O, Sato S, Kufta CV et al. Electroencephalographic studies of simple partial seizures with subdural electrode recordings. Neurology 39(4), 527-533 (1989). (Pubitemid 19105768)
109. Hoppe C, Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch. Neurol. 64(11), 1595-1599 (2007). (Pubitemid 350106760)
110. Doelken MT, Stefan H, Pauli E et al. (1) H-MRS profile in MRI positive-versus MRI negative patients with temporal lobe epilepsy. Seizure 17(6), 490-497 (2008).
111. Holmes MD, Tucker DM, Quiring JM, Hakimian S, Miller JW, Ojemann JG. Comparing noninvasive dense array and intracranial electroencephalography for localization of seizures. Neurosurgery 66(2), 354-362 (2010).
112. Pitkanen A, Lukasiuk K. Molecular biomarkers of epileptogenesis. Biomark. Med. 5(5), 629-633 (2011).
113. Holtman L, van Vliet EA, Aronica E, Wouters D, Wadman WJ, Gorter JA. Blood plasma inflammation markers during epileptogenesis in post-status epilepticus rat model for temporal lobe epilepsy. Epilepsia 54(4), 589-595 (2013).
114. Klitgaard H, Loscher W, Twyman RE, Schmidt D. New avenues for antiepileptic drug discovery and development: a joint endeavor of academia and industry. Nature Rev. Drug Discovery (2013) (In Press).
115. Chan A, Pirmohamed M, Comabella M. Pharmacogenomics in neurology: current state and future steps. Ann. Neurol. 70(5), 684-697 (2011).
116. Gomes WA, Shinnar S. Prospects for imaging-related biomarkers of human epileptogenesis: a critical review. Biomark. Med. 5(5), 599-606 (2011).
117. Staba RJ, Bragin A. High-frequency oscillations and other electrophysiological biomarkers of epilepsy: underlying mechanisms. Biomark. Med. 5(5), 545-556 (2011).
118. Blumenfeld H, Klein JP, Schridde U et al. Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49(3), 400-409 (2008). (Pubitemid 351294541)
119. Dezsi G, Ozturk E, Stanic D et al. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54(4), 635-643 (2013).
120. Russo E, Citraro R, Scicchitano F et al. Comparison of the antiepileptogenic effects of an early long-term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy. Epilepsia 51(8), 1560-1569 (2010).
121. Russo E, Citraro R, Donato G et al. mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology 69, 25-36 (2013).
122. Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia 53(7), 1119-1130 (2012).
123. Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 10(5), 446-456 (2011).
124. Perucca E, French J, Bialer M. Development of new antiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol. 6(9), 793-804 (2007). (Pubitemid 47243712)
125. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 103(1), 2-30 (2013).
126. Paul SM, Mytelka DS, Dunwiddie CT et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9(3), 203-214 (2010).
127. Perucca E. What clinical trial designs have been used to test antiepileptic drugs and do we need to change them? Epileptic Disord. 14(2), 124-131 (2012).
128. Friedman D, French JA. Clinical trials for therapeutic assessment of antiepileptic drugs in the 21st century: obstacles and solutions. Lancet Neurol. 11(9), 827-834 (2012).
129. Ajmone-Cat MA, Bernardo A, Greco A, Minghetti L. Non-steroidal anti-inflammatory drugs and brain inflammation: effects on microglial functions. Pharmaceuticals 3(6), 1949-1965 (2010).
130. Ma L, Cui XL, Wang Y et al. Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res. 1469, 103-113 (2012).
131. Gaur V, Kumar A. Effect of nonselective and selective COX-2 inhibitors on memory dysfunction, glutathione system, and tumor necrosis factor alpha level against cerebral ischemia reperfusion injury. Drug Chem. Toxicol. 35(2), 218-224 (2012).
132. Jung KH, Chu K, Lee ST et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpineinduced status epilepticus. Neurobiol. Dis. 23(2), 237-246 (2006). (Pubitemid 44097031)
133. Chao PK, Lu KT, Jhu JY et al. Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1b release through the inhibition of Nogo-A expression. J. Neuroinflammation 9, 121 (2012).
134. Girgis H, Palmier B, Croci N, Soustrat M, Plotkine M, Marchand-Leroux C. Effects of selective and non-selective cyclooxygenase inhibition against neurological deficit and brain oedema following closed head injury in mice. Brain Res. 1491, 78-87 (2013).
135. Dhir A, Naidu PS, Kulkarni SK. Neuroprotective effect of nimesulide, a preferential COX-2 inhibitor, against pentylenetetrazol (PTZ)-induced chemical kindling and associated biochemical parameters in mice. Seizure 16(8), 691-697 (2007). (Pubitemid 350018665)
136. Candelario-Jalil E. Nimesulide as a promising neuroprotectant in brain ischemia: new experimental evidences. Pharmacol. Res. 57(4), 266-273 (2008).
137. Polascheck N, Bankstahl M, Loscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp. Neurol. 224(1), 219-233 (2010).
138. Wang Q, Yan J, Chen X et al. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp. Neurol. 230(1), 27-34 (2011).
139. Wible EF, Laskowitz DT. Statins in traumatic brain injury. Neurotherapeutics 7(1), 62-73 (2010).
140. Lu D, Goussev A, Chen J et al. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J. Neurotrauma 21(1), 21-32 (2004). (Pubitemid 38141799)
141. Chauhan NB, Gatto R. Restoration of cognitive deficits after statin feeding in TBI. Restor. Neurol. Neurosci. 29(1), 23-34 (2011).
142. Indraswari F, Wang H, Lei B et al. Statins improve outcome in murine models of intracranial hemorrhage and traumatic brain injury: a translational approach. J. Neurotrauma 29(7), 1388-1400 (2012).
143. Mahmood A, Goussev A, Kazmi H, Qu C, Lu D, Chopp M. Long-term benefits after treatment of traumatic brain injury with simvastatin in rats. Neurosurgery 65(1), 187-191; discussion 191 (2009).
144. Xie C, Sun J, Qiao W et al. Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy. PLoS ONE 6(9), e24966 (2011).
145. Fleischmann R, Stern R, Iqbal I. Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis. Expert Opin. Biol. Ther. 4(8), 1333-1344 (2004). (Pubitemid 39005738)
146. Pradillo JM, Denes A, Greenhalgh AD et al. Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J. Cereb. Blood Flow Metab. 32(9), 1810-1819 (2012).
147. Arcasoy MO. The non-haematopoietic biological effects of erythropoietin. Br. J. Haematol. 141(1), 14-31 (2008). (Pubitemid 351347536)
148. Jung KH, Chu K, Lee ST et al. Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin. Epilepsia 52(3), 541-550 (2011).
149. Chu K, Jung KH, Lee ST et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 49(10), 1723-1732 (2008).
150. Rabie T, Marti HH. Brain protection by erythropoietin: a manifold task. Physiology (Bethesda) 23, 263-274 (2008).
151. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neuroprotective agent. Neuroscientist 11(4), 308-322 (2005). (Pubitemid 41040860)
152. Kovesdi E, Kamnaksh A, Wingo D et al. Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front. Neurol. 3, 111 (2012).
153. Tintinger GR, Feldman C, Theron AJ, Anderson R. Montelukast: more than a cysteinyl leukotriene receptor antagonist? Scientific World J. 10, 2403-2413 (2010).
154. Zhao R, Shi WZ, Zhang YM, Fang SH, Wei EQ. Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats. J. Pharm. Pharmacol. 63(4), 550-557 (2011).
155. Brinton RD, Thompson RF, Foy MR et al. Progesterone receptors: form and function in brain. Front. Neuroendocrinol. 29(2), 313-339 (2008).
156. Weichhart T, Costantino G, Poglitsch M et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29(4), 565-577 (2008).
157. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin. Pharmacol. Ther. 82(4), 381-388 (2007). (Pubitemid 47414349)
158. Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26(1), 86-93 (2007). (Pubitemid 46436489)
159. Park J, Zhang J, Qiu J et al. Combination therapy targeting Akt and mammalian target of rapamycin improves functional outcome after controlled cortical impact in mice. J. Cereb. Blood Flow Metab. 32(2), 330-340 (2012).
160. Sunnen CN, Brewster AL, Lugo JN et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia 52(11), 2065-2075 (2011).
161. Russo E, Citraro R, Constanti A, De Sarro G. The mTOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. Mol. Neurobiol. 46(3), 662-681 (2012).
162. Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K. Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci. Lett. 509(2), 105-109 (2012).
163. Kumar V, Chhibber S. Thalidomide: an old drug with new action. J. Chemother. 23(6), 326-334 (2011).
164. Zhang L, Qu Y, Tang J et al. PI3K/Akt signaling pathway is required for neuroprotection of thalidomide on hypoxic-ischemic cortical neurons in vitro. Brain Res. 1357, 157-165 (2010).
165. Hyakkoku K, Nakajima Y, Izuta H et al. Thalidomide protects against ischemic neuronal damage induced by focal cerebral ischemia in mice. Neuroscience 159(2), 760-769 (2009).