Epilepsy Benchmark IC1

2005 Report submitted by Benchmark Steward(s):
H. Steve White, Ph.D. (University of Utah)
James Stables, M.S.A. (National Institute of Neurological Disorders and Stroke)

Background of the benchmark goal:  As with all classes of drugs, the discovery and development of new AEDs rely heavily on the employment of preclinical models to demonstrate efficacy and safety prior to their introduction into human volunteers.  Obviously, the more predictive an animal model(s) for a particular seizure type or syndrome, the greater the likelihood that the investigational AED will demonstrate efficacy in human clinical trials.  Herein lies one of the most often discussed issues in the current-day AED discovery process; i.e., what is the most appropriate in vivo/ in vitro model system(s) to employ when attempting to find comparable efficacy in human epilepsy patients? 

Current status of field:  Since 1993, nine new AEDs have been introduced for the management of partial epilepsy. Currently there are also several new compounds in various stages of clinical development. These discoveries and their subsequent development have predominately been based on activity either the maximal electroshock, s.c. Metrazol, or kindled rat models of generalized and partial seizures.  Their introduction into the treatment armamentarium has clearly had an impact on the lives of patients with epilepsy through improved seizure control, a lessening of adverse events, improved pharmacokinetics, and fewer drug-drug interactions.  Unfortunately, despite the availability of these new therapeutic options, a significant fraction of the patients with epilepsy continue to live with uncontrolled seizures, often at the expense of significant drug-induced adverse events.  Clearly, there is a need for more efficacious therapies that will not infringe on a patient’s quality of life.  The successful identification of more effective drugs will depend on the identification and validation of models that more closely resemble human epilepsy.             

Activities update: 

• Planning for a Models Task Force Meeting to review progress/barriers in models for antiepileptogenesis (AEG) along with unique pharmacology in the pediatric and elderly systems.
• Awarded 6 grants in the area of AEG and pharmacoresistance (PR). Also, people are now reporting numerous research activities in the area of AEG & PR.

Top priorities for next 5-10 years:

• Develop a community-wide data base of pharmacological results forthcoming from RFA supported grants
• Define a mechanism for selecting and testing investigational therapy in newly defined epilepsy model (Task Force topic)
• Determine the feasibility for incorporation of newly identified and validated model systems of AEG & PR into NINDS sponsored screening program testing the most novel candidates to these new systems.
• Continue to shepherd efforts to support model development for catastrophic pediatric epilepsies and geriatric epilepsy that can be incorporated into therapy screening programs. 
• Develop a consortium of investigators that have an expressed interest in characterizing novel therapeutics in a more diverse battery of the highly labor intensive, low throughput animal models
• Develop collaboration with other Benchmark Stewards in an effort to incorporate novel findings into ongoing therapy discovery programs             

Roadblocks to progress:

• Low through-put associated with most chronic epilepsy animal models
• Recognition that translational support will promote progress in both basic and clinical outcomes.
• Lack of validated miniaturized video-telemetry recording units that can be employed in genetic mouse models.  Need to develop and apply new technology in these areas.
• Paucity of laboratories interested in conducting therapy screening and trained whole animal pharmacologists with expressed interest in translational research.

References:

1. Grabenstatter HL, Ferraro DJ, Williams PA, Chapman PL, Dudek FE. Use of Chronic Epilepsy Models in Antiepileptic Drug Discovery: The Effect of Topiramate on Spontaneous Motor Seizures in Rats with Kainate-induced Epilepsy. Epilepsia. 2005 Jan;46(1):814.
2. Brandt C, Volk HA, Loscher W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia. 2004 Dec;45(12):1488-97.
3. Kudin AP, Debska-Vielhaber G, Vielhaber S, Elger CE, Kunz WS. The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia. 2004 Dec;45(12):1478-87.
4. Dube C, Yu H, Nalcioglu O, Baram TZ. Serial MRI after experimental febrile seizures: altered T2 signal without neuronal death. Ann Neurol. 2004 Nov;56(5):709-14.
5. Fisher A, Wang X, Cock HR, Thom M, Patsalos PN, Walker MC. Synergism between topiramate and budipine in refractory status epilepticus in the rat. Epilepsia. 2004 Nov;45(11):1300-7.
6. Buckmaster PS. Laboratory animal models of temporal lobe epilepsy.
   Comp Med. 2004 Oct;54(5):473-85.
7. Williams AJ, Tortella FC, Lu XM, Moreton JE, Hartings JA. Antiepileptic drug treatment of nonconvulsive seizures induced by experimental focal brain ischemia. J Pharmacol Exp Ther. 2004 Oct;311(1):220-7. Epub 2004 May 12.
8. Potschka H, Volk HA, Loscher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. Neuroreport. 2004 Jul 19;15(10):1657-61.
9. He XP, Kotloski R, Nef S, Luikart BW, Parada LF, McNamara JO. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron. 2004 Jul 8;43(1):31-42.
10. Majores M, Eils J, Wiestler OD, Becker AJ. Molecular profiling of temporal lobe epilepsy: comparison of data from human tissue samples and animal models. Epilepsy Res. 2004 Jul-Aug;60(2-3):173-8. Review.
11. Stanojlovic OP, Zivanovic DP.  [Experimental models of epilepsy]
    Med Pregl. 2004 Jul-Aug;57(7-8):359-62.  Serbian.
12. Graber KD, Prince DA. A critical period for prevention of posttraumatic neocortical hyperexcitability in rats. Ann Neurol. 2004 Jun;55(6):860-70.
13. Leroy C, Poisbeau P, Keller AF, Nehlig A. Pharmacological plasticity of GABA(A) receptors at dentate gyrus synapses in a rat model of temporal lobe epilepsy. J Physiol. 2004 Jun 1;557(Pt 2):473-87. Epub 2004 Mar 19.
14. Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol. 2004 May;73(1):1-60. Review.
15. Richichi C, Lin EJ, Stefanin D, Colella D, Ravizza T, Grignaschi G, Veglianese P, Sperk G, During MJ, Vezzani A. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci. 2004 Mar 24;24(12):3051-9.
16. Ratzliff AH, Howard AL, Santhakumar V, Osapay I, Soltesz I. Rapid deletion of mossy cells does not result in a hyperexcitable dentate gyrus: implications for epileptogenesis. J Neurosci. 2004 Mar 3;24(9):2259-69.
17. Nilsen KE, Cock HR. Focal treatment for refractory epilepsy: hope for the future? Brain Res Brain Res Rev. 2004 Mar;44(2-3):141-53. Review.
18. Lyon A, Marone S, Wainman D, Weaver DF. Implementing a bioassay to screen molecules for antiepileptogenic activity: chronic pilocarpine versus subdudral haematoma models. Seizure. 2004 Mar;13(2):82-6.
19. D'Ambrosio R, Fairbanks JP, Fender JS, Born DE, Doyle DL, Miller JW. Post-traumatic epilepsy following fluid percussion injury in the rat. Brain. 2004 Feb;127(Pt 2):304-14. Epub 2003 Nov 07.
20. Lazarowski A, Ramos AJ, Garcia-Rivello H, Brusco A, Girardi E. Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model. Cell Mol Neurobiol. 2004 Feb;24(1):77-85.
21. Solbrig MV, Koob GF. Epilepsy, CNS viral injury and dynorphin.
    Trends Pharmacol Sci. 2004 Feb;25(2):98-104. Review.
22. Gouder N, Scheurer L, Fritschy JM, Boison D. Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis. J Neurosci. 2004 Jan 21;24(3):692-701.
23. Benke TA, Swann J. The tetanus toxin model of chronic epilepsy. Adv Exp Med Biol. 2004;548:226-38. Review.
24. Bender RA, Dube C, Baram TZ. Febrile seizures and mechanisms of epileptogenesis: insights from an animal model. Adv Exp Med Biol. 2004;548:213-25. Review.
25. Schwartzkroin PA, Roper SN, Wenzel HJ. Cortical dysplasia and epilepsy: animal models. Adv Exp Med Biol. 2004;548:145-74. Review.
26. Yang Y, Frankel WN. Genetic approaches to studying mouse models of human seizure disorders. Adv Exp Med Biol. 2004;548:1-11. Review.
27. Halasz P, Rasonyi G. Neuroprotection and epilepsy. Adv Exp Med Biol. 2004;541:91-109. Review.
28. Rho JM. Basic science behind the catastrophic epilepsies. Epilepsia. 2004;45 Suppl 5:5-11. Review.
29. Thompson KW, Suchomelova LM. Transplants of cells engineered to produce GABA suppress spontaneous seizures. Epilepsia. 2004 Jan;45(1):4-12.
30. Niittykoski M, Nissinen J, Penttonen M, Pitkanen A. Electrophysiologic changes in the lateral and basal amygdaloid nuclei in temporal lobe epilepsy: an in vitro study in epileptic rats. Neuroscience. 2004;124(2):269-81.
31. Quilichini PP, Diabira D, Chiron C, Milh M, Ben-Ari Y, Gozlan H. Effects of antiepileptic drugs on refractory seizures in the intact immature corticohippocampal formation in vitro. Epilepsia. 2003 Nov;44(11):1365-74.
32. Zhao WJ, Ma YH, Fei J, Mei ZT, Guo LH. Increase in drug-induced seizure susceptibility of transgenic mice overexpressing GABA transporter-1. Acta Pharmacol Sin. 2003 Oct;24(10):991-5.
33. Lauren HB, Pitkanen A, Nissinen J, Soini SL, Korpi ER, Holopainen IE. Selective changes in gamma-aminobutyric acid type A receptor subunits in the hippocampus in spontaneously seizing rats with chronic temporal lobe epilepsy. Neurosci Lett. 2003 Sep 25;349(1):58-62.
34. Lagae L, Buyse G, Ceulemans B, Claeys P, Dedeurwaerdere S, de Meirleir L, Hauman R, Janssen A, Schmedding E, Verhelst H, Vonck K. Anti-epileptogenesis research: the clinical relevance. Acta Neurol Belg. 2003 Jun;103(2):78-82. Review.
35. Klitgaard H, Pitkanen A. Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam. Epileptic Disord. 2003 May;5 Suppl 1:S9-16. Review.
36. Remy S, Gabriel S, Urban BW, Dietrich D, Lehmann TN, Elger CE, Heinemann U, Beck H. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol. 2003 Apr;53(4):469-79.
37. Sisodiya SM. Mechanisms of antiepileptic drug resistance. Curr Opin Neurol. 2003 Apr;16(2):197-201. Review.
38. Wang Y, Zhou D, Wang B, Li H, Chai H, Zhou Q, Zhang S, Stefan H. A kindling model of pharmacoresistant temporal lobe epilepsy in Sprague-Dawley rats induced by Coriaria lactone and its possible mechanism. Epilepsia. 2003 Apr;44(4):475-88.
39. Rigoulot MA, Leroy C, Koning E, Ferrandon A, Nehlig A. Prolonged low-dose caffeine exposure protects against hippocampal damage but not against the occurrence of epilepsy in the lithium-pilocarpine model in the rat. Epilepsia. 2003 Apr;44(4):529-35.
40. Elliott RC, Miles MF, Lowenstein DH. Overlapping microarray profiles of dentate gyrus gene expression during development- and epilepsy-associated neurogenesis and axon outgrowth. J Neurosci. 2003 Mar 15;23(6):2218-27.
41. Upton N, Stratton S. Recent developments from genetic mouse models of seizures. Curr Opin Pharmacol. 2003 Feb;3(1):19-26. Review.
42. Benardo LS. Prevention of epilepsy after head trauma: do we need new drugs or a new approach? Epilepsia. 2003;44 Suppl 10:27-33. Review.
43. White HS. Preclinical development of antiepileptic drugs: past, present, and future directions. Epilepsia. 2003;44 Suppl 7:2-8. Review.
44. Reibel S, Benmaamar R, Le BT, Larmet Y, Kalra SP, Marescaux C, Depaulis A. Neuropeptide Y delays hippocampal kindling in the rat. Hippocampus. 2003;13(5):557-60.
45. Brandt C, Potschka H, Loscher W, Ebert U. N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy. Neuroscience. 2003;118(3):727-40.
46. Kelly KM. Poststroke Seizures and Epilepsy: Clinical Studies and Animal Models. Epilepsy Curr. 2002 Nov;2(6):173-177.
47. Stables J.P., Bertram E.H., White H.S., Coulter D.A., Dichter M.A., Jacobs M.P., Loscher W., Lowenstein D.H., Moshe S.L., Noebels J.L., and Davis M.  Models for epilepsy and epileptogenesis:  report from the NIH workshop, Bethesda, Maryland.  Epilepsia.  43(11)1410-1420, 2002.
48. Stables J.P., Bertram E., Dudek F.E., Holmes G., Mathern G., Pitkanen A., and White HS.  Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics:  Summary of the NIH/NINDS/AES Models II Workshop.  Epilepsia.  44(12): 1472-1478, 2003.