AMPA 受体及其拮抗剂在癫痫持续状态中的作用_Journal of Epilepsy

Authors：

AntonioLeo , GiadaGiovannini ,  EmilioRusso , 张乐　译 , 熊维希　慕洁　审

Corresponding author：

EmilioRusso, Email: erusso@unicz.it

Keywords：

α-氨基-3-羟基-5-羟基-5-甲基-4-异恶唑丙酸受体; 动物模型; 谷氨酸受体; 吡仑帕奈; 难治性癫痫持续状态; 癫痫持续状态的治疗

DOI：

10.7507/2096-0247.20200027

Video：

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癫痫持续状态（Status epilepticus，SE）通常定义为长时间持续的癫痫发作或反复发作且发作间期未完全恢复。SE 是一种急症，通常与严重的残疾、较高的发病率和死亡率相关。尽管受临床的影响，但从自限性癫痫发作过渡到持续的、难治性的癫痫发作的潜在机制仍尚不完全明确。在 SE 中，约 40%的患者对抗癫痫药物（AEDs）（一线治疗）无效；因此，需要更有效的药物。在这篇综述中，我们着重于目前对于 α-氨基-3-羟基-5-羟基-5-甲基-4-异恶唑丙酸（alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid，AMPA）受体在 SE 中作用的了解，以及其拮抗剂的临床前功效和当前发表的涉及具有这种作用机制的药物的临床研究。我们对关于 AMPA 受体、AMPA 受体拮抗剂和 SE 的实验性和临床研究文章进行了全面的文献检索。近年来，AMPA 受体在 SE 发作期间和发作后的作用变得逐渐清晰，现在已被广泛接受的是其早期变化发生在初始阶段，这可能有导致 SE 的维持及其对治疗的抵抗性。AMPA 受体拮抗剂已在几种 SE 动物模型中被证实可终止发作，这些研究支持着抑制 AMPA 受体的治疗潜力。迄今为止，人体研究的相关数据很有限，但前景广阔，它们支持在 SE 患者中使用 AMPA 受体拮抗剂。当二线药物首次尝试失败后，AMPA 受体拮抗剂可能成为确定的 SE 患者的新治疗选择，特别是在苯二氮卓作为二线治疗失败后，甚至效果可能更好。

Citation： AntonioLeo, GiadaGiovannini, EmilioRusso, 张乐　译, 熊维希　慕洁　审. AMPA 受体及其拮抗剂在癫痫持续状态中的作用. Journal of Epilepsy, 2020, 6(2): 157-165. doi: 10.7507/2096-0247.20200027 Copy

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4.	Giovannini G, Monti G, Polisi MM, et al. A one-year prospective study of refractory status epilepticus in Modena, Italy. Epilepsy Behav, 2015, 49(1): 141-145.
5.	Kortland LM, Alfter A, Bahr O, et al. Costs and cost-driving factors for acute treatment of adults with status epilepticus: a multicenter cohort study from Germany. Epilepsia, 2016, 57(12): 2056-2066.
6.	Goodkin HP, Joshi S, Mtchedlishvili Z, et al. Subunit-specific trafficking of GABA(A) receptors during status epilepticus. J Neurosci, 2008, 28(12): 2527-2538.
7.	Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci, 2005, 25(2): 7724-7733.
8.	Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol, 2006, 5(2): 246-256.
9.	Naylor DE. Glutamate and GABA in the balance: convergent pathways sustain seizures during status epilepticus. Epilepsia, 2010, 51(Suppl 3): 106-109.
10.	Deeb TZ, Maguire J, Moss SJ. Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia, 2012, 53(Suppl 9): 79-88.
11.	Trinka E, Hofler J, Leitinger M, et al. Pharmacotherapy for status epilepticus. Drugs, 2015, 75(7): 1499-1521.
12.	Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol, 2006, 13(2): 445-450.
13.	Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol, 2005, 62(8): 1698-1702.
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28.	Brill J, Huguenard JR. Sequential changes in AMPA receptor targeting in the developing neocortical excitatory circuit. J Neurosci, 2008, 28(6): 13918-13928.
29.	Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol, 2009, 5(2): 380-391.
30.	Talos DM, Fishman RE, Park H, et al. Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol, 2006, 497(1): 42-60.
31.	Pellegrini-Giampietro DE, Gorter JA, Bennett MV, et al. The GluR2 (GluR-B) hypothesis Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci, 1997, 20(3): 464-470.
32.	Liu SJ, Zukin RS. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci, 2007, 30(1): 126-134.
33.	Condorelli DF, Belluardo N, Mudo G, et al. Changes in gene expression of AMPA-selective glutamate receptor subunits induced by status epilepticus in rat brain. Neurochem Int, 1994, 25(2): 367-376.
34.	Hu Y, Jiang L, Chen H, et al. Expression of AMPA receptor subunits in hippocampus after status convulsion. Childs Nerv Syst, 2012, 28(4): 911-918.
35.	Rajasekaran K, Todorovic M, Kapur J. Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol, 2012, 72(1): 91-102.
36.	Friedman LK. Selective reduction of GluR2 protein in adult hippocampal CA3 neurons following status epilepticus but prior to cell loss. Hippocampus, 1998, 8(3): 511-525.
37.	Grooms SY, Opitz T, Bennett MV, et al. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc Natl Acad Sci USA, 2000, 97(12): 3631-3636.
38.	Walton NY, Treiman DM. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol, 1988, 101(2): 267-275.
39.	Russo I, Bonini D, Via LL, et al. AMPA receptor properties are modulated in the early stages following pilocarpine-induced status epilepticus. Neuromolecular Med, 2013, 15(2): 324-338.
40.	Lopes MW, Soares FM, de Mello N, et al. Time-dependent modulation of AMPA receptor phosphorylation and mRNA expression of NMDA receptors and glial glutamate transporters in the rat hippocampus and cerebral cortex in a pilocarpine model of epilepsy. Exp Brain Res, 2013, 226(1): 153-163.
41.	Malkin SL, Amakhin DV, Veniaminova EA, et al. Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats. Neuroscience, 2016, 327(1): 146-155.
42.	Szczurowska E, Ergang P, Kubova H, et al. Influence of early life status epilepticus on the developmental expression profile of the GluA2 subunit of AMPA receptors. Exp Neurol, 2016, 283(1): 97-109.
43.	Loddenkemper T, Talos DM, Cleary RT, et al. Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus. Epilepsy Res, 2014, 108(3): 605-615.
44.	Morrell F, de Toledo-Morrell L. From mirror focus to secondary epileptogenesis in man: an historical review. Adv Neurol, 1999, 81(1): 11-23.
45.	Sobayo T, Mogul DJ. Rapid onset of a kainate-induced mirror focus in rat hippocampus is mediated by contralateral AMPA receptors. Epilepsy Res, 2013, 106(1): 35-46.
46.	Pitkanen A, Mathiesen C, Ronn LC, et al. Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat. Epilepsy Res, 2007, 74(1): 45-54.
47.	Fritsch B, Stott JJ, Joelle Donofrio J, et al. Treatment of early and late kainic acid-induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466. Epilepsia, 2010, 51(1): 108-117.
48.	Langer M, Brandt C, Zellinger C, et al. Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats. Neuropharmacology, 2011, 61(5): 1033-1047.
49.	Hanada T, Ido K, Kosasa T. Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model. Pharmacol Res Perspect, 2014, 2: e00063.
50.	Palleria C, Coppola A, Citraro R, et al. Perspectives on treatment options for mesial temporal lobe epilepsy with hippocampal sclerosis. Expert Opin Pharmacother, 2015, 16(12): 2355-2371.
51.	Di Bonaventura C, Labate A, Maschio M, et al. AMPA receptors and perampanel behind selected epilepsies current evidence and future perspectives. Expert Opin Pharmacother, 2017, 18(1): 1-14.
52.	Dhir A, Chavda V. Pre- and post-exposure talampanel (GYKI 53773) against kainic acid seizures in neonatal rats. Pharmacol Rep, 2016, 68(2): 190-195.
53.	Franco V, Crema F, Iudice A, et al. Novel treatment options for epilepsy: focus on perampanel. Pharmacol Res, 2013, 70(1): 35-40.
54.	Redecker J, Wittstock M, Benecke R, et al. Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus. Epilepsy Behav, 2015, 45(1): 176-179.
55.	Blackburn-Munro G, Bomholt SF, Erichsen HK. Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain. Neuropharmacology, 2004, 47(2): 351-362.
56.	Sabers A, Wolf P, Moller A, et al. A prospective, randomized, multicentre trial for the treatment of refractory status epilepticus, experiences from evaluating the effect of the novel drug candidate, NS1209. Epilepsy Res, 2013, 106(2): 292-295.
57.	Rossetti AO, Holtkamp M. Selection bias in analysis of status epilepticus in the intensive care unit. Crit Care Med, 2011, 39(4): 927–928, author reply 928.
58.	Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol, 2011, 10(4): 922-930.
59.	Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med, 2012, 366(3): 591-600.
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1. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus-report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia, 2015, 56(8): 1515-1523.
2. Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lan cet Neurol, 2015, 14(3): 615-624.
3. Trinka E, Kalviainen R. 25 years of advances in the definition, classification and treatment of status epilepticus. Seizure, 2017, 44(1): 65-73.
4. Giovannini G, Monti G, Polisi MM, et al. A one-year prospective study of refractory status epilepticus in Modena, Italy. Epilepsy Behav, 2015, 49(1): 141-145.
5. Kortland LM, Alfter A, Bahr O, et al. Costs and cost-driving factors for acute treatment of adults with status epilepticus: a multicenter cohort study from Germany. Epilepsia, 2016, 57(12): 2056-2066.
6. Goodkin HP, Joshi S, Mtchedlishvili Z, et al. Subunit-specific trafficking of GABA(A) receptors during status epilepticus. J Neurosci, 2008, 28(12): 2527-2538.
7. Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci, 2005, 25(2): 7724-7733.
8. Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol, 2006, 5(2): 246-256.
9. Naylor DE. Glutamate and GABA in the balance: convergent pathways sustain seizures during status epilepticus. Epilepsia, 2010, 51(Suppl 3): 106-109.
10. Deeb TZ, Maguire J, Moss SJ. Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia, 2012, 53(Suppl 9): 79-88.
11. Trinka E, Hofler J, Leitinger M, et al. Pharmacotherapy for status epilepticus. Drugs, 2015, 75(7): 1499-1521.
12. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol, 2006, 13(2): 445-450.
13. Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol, 2005, 62(8): 1698-1702.
14. Hocker S, Wijdicks EF, Rabinstein AA. Refractory status epilepticus: new insights in presentation, treatment, and outcome. Neurol Res, 2013, 35(1): 163-168.
15. Sutter R, Marsch S, Fuhr P, et al. Mortality and recovery from refractory status epilepticus in the intensive care unit: a 7-year observational study. Epilepsia, 2013, 54(3): 502-511.
16. Citraro R, Aiello R, Franco V, et al. Targeting alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors in epilepsy. Expert Opin Ther Targets, 2014, 18(2): 319-334.
17. Citraro R, Leo A, Franco V, et al. Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior. Epilepsia, 2017, 58(1): 231-238.
18. Russo E, Citraro R, Constanti A, et al. Upholding WAG/Rij rats as a model of absence epileptogenesis: hidden mechanisms and a new theory on seizure development. Neurosci Biobehav Rev, 2016, 71(2): 388-408.
19. Rogawski MA. AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol Scand Suppl, 2013, 197(1): 9-18.
20. Dupuis N, Enderlin J, Thomas J, et al. Anti-ictogenic and antiepileptogenic properties of perampanel in mature and immature rats. Epilepsia, 2017, 58(9): 1985-1992.
21. Russo E, Gitto R, Citraro R, et al. New AMPA antagonists in epilepsy. Expert Opin Investig Drugs, 2012, 21(6): 1371-1389.
22. Dingledine R. Glutamatergic mechanisms related to epilepsy: ionotropic receptors. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper’s basic mechanisms of the epilepsies. Bethesda, MD: National Center for Biotechnology Information, 2012: 163–176.
23. Nicoletti F, Bockaert J, Collingridge GL, et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology, 2011, 60(5): 1017-1041.
24. DeLorenzo RJ, Sun DA. Basic mechanisms in status epilepticus: role of calcium in neuronal injury and the induction of epileptogenesis. Adv Neurol, 2006, 97(1): 187-197.
25. Huberfeld G, Menendez de la Prida L, Pallud J, et al. Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy. Nat Neurosci, 2011, 14(3): 627-634.
26. Traynelis SF, Wollmuth LP, McBain CJ, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev, 2010, 62(2): 405-496.
27. Cull-Candy S, Kelly L, Farrant M. Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond. Curr Opin Neurobiol, 2006, 16(2): 288-297.
28. Brill J, Huguenard JR. Sequential changes in AMPA receptor targeting in the developing neocortical excitatory circuit. J Neurosci, 2008, 28(6): 13918-13928.
29. Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol, 2009, 5(2): 380-391.
30. Talos DM, Fishman RE, Park H, et al. Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol, 2006, 497(1): 42-60.
31. Pellegrini-Giampietro DE, Gorter JA, Bennett MV, et al. The GluR2 (GluR-B) hypothesis Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci, 1997, 20(3): 464-470.
32. Liu SJ, Zukin RS. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci, 2007, 30(1): 126-134.
33. Condorelli DF, Belluardo N, Mudo G, et al. Changes in gene expression of AMPA-selective glutamate receptor subunits induced by status epilepticus in rat brain. Neurochem Int, 1994, 25(2): 367-376.
34. Hu Y, Jiang L, Chen H, et al. Expression of AMPA receptor subunits in hippocampus after status convulsion. Childs Nerv Syst, 2012, 28(4): 911-918.
35. Rajasekaran K, Todorovic M, Kapur J. Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol, 2012, 72(1): 91-102.
36. Friedman LK. Selective reduction of GluR2 protein in adult hippocampal CA3 neurons following status epilepticus but prior to cell loss. Hippocampus, 1998, 8(3): 511-525.
37. Grooms SY, Opitz T, Bennett MV, et al. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc Natl Acad Sci USA, 2000, 97(12): 3631-3636.
38. Walton NY, Treiman DM. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol, 1988, 101(2): 267-275.
39. Russo I, Bonini D, Via LL, et al. AMPA receptor properties are modulated in the early stages following pilocarpine-induced status epilepticus. Neuromolecular Med, 2013, 15(2): 324-338.
40. Lopes MW, Soares FM, de Mello N, et al. Time-dependent modulation of AMPA receptor phosphorylation and mRNA expression of NMDA receptors and glial glutamate transporters in the rat hippocampus and cerebral cortex in a pilocarpine model of epilepsy. Exp Brain Res, 2013, 226(1): 153-163.
41. Malkin SL, Amakhin DV, Veniaminova EA, et al. Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats. Neuroscience, 2016, 327(1): 146-155.
42. Szczurowska E, Ergang P, Kubova H, et al. Influence of early life status epilepticus on the developmental expression profile of the GluA2 subunit of AMPA receptors. Exp Neurol, 2016, 283(1): 97-109.
43. Loddenkemper T, Talos DM, Cleary RT, et al. Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus. Epilepsy Res, 2014, 108(3): 605-615.
44. Morrell F, de Toledo-Morrell L. From mirror focus to secondary epileptogenesis in man: an historical review. Adv Neurol, 1999, 81(1): 11-23.
45. Sobayo T, Mogul DJ. Rapid onset of a kainate-induced mirror focus in rat hippocampus is mediated by contralateral AMPA receptors. Epilepsy Res, 2013, 106(1): 35-46.
46. Pitkanen A, Mathiesen C, Ronn LC, et al. Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat. Epilepsy Res, 2007, 74(1): 45-54.
47. Fritsch B, Stott JJ, Joelle Donofrio J, et al. Treatment of early and late kainic acid-induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466. Epilepsia, 2010, 51(1): 108-117.
48. Langer M, Brandt C, Zellinger C, et al. Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats. Neuropharmacology, 2011, 61(5): 1033-1047.
49. Hanada T, Ido K, Kosasa T. Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model. Pharmacol Res Perspect, 2014, 2: e00063.
50. Palleria C, Coppola A, Citraro R, et al. Perspectives on treatment options for mesial temporal lobe epilepsy with hippocampal sclerosis. Expert Opin Pharmacother, 2015, 16(12): 2355-2371.
51. Di Bonaventura C, Labate A, Maschio M, et al. AMPA receptors and perampanel behind selected epilepsies current evidence and future perspectives. Expert Opin Pharmacother, 2017, 18(1): 1-14.
52. Dhir A, Chavda V. Pre- and post-exposure talampanel (GYKI 53773) against kainic acid seizures in neonatal rats. Pharmacol Rep, 2016, 68(2): 190-195.
53. Franco V, Crema F, Iudice A, et al. Novel treatment options for epilepsy: focus on perampanel. Pharmacol Res, 2013, 70(1): 35-40.
54. Redecker J, Wittstock M, Benecke R, et al. Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus. Epilepsy Behav, 2015, 45(1): 176-179.
55. Blackburn-Munro G, Bomholt SF, Erichsen HK. Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain. Neuropharmacology, 2004, 47(2): 351-362.
56. Sabers A, Wolf P, Moller A, et al. A prospective, randomized, multicentre trial for the treatment of refractory status epilepticus, experiences from evaluating the effect of the novel drug candidate, NS1209. Epilepsy Res, 2013, 106(2): 292-295.
57. Rossetti AO, Holtkamp M. Selection bias in analysis of status epilepticus in the intensive care unit. Crit Care Med, 2011, 39(4): 927–928, author reply 928.
58. Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol, 2011, 10(4): 922-930.
59. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med, 2012, 366(3): 591-600.
60. Rosenthal ES, Claassen J, Wainwright MS, et al. Brexanolone as adjunctive therapy in super-refractory status epilepticus. Ann Neurol, 2017, 82(2): 342-352.
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