靶向腦源性神經營養因子/酪氨酸激酶 B 信號通路對癲癇的抑制_Journal of Epilepsy

Authors：

張冉冉 , 王珂黙 , 石燕婷 , 杜倩雯 ,  劉學伍

山東大學齊魯醫院神經內科（濟南 250012）;

Corresponding?author：

劉學伍, Email: snlxw1966@163.com

Keywords：

顳葉癲癇; 創傷后癲癇; 腦源性神經營養因子; 酪氨酸激酶 B

DOI：

10.7507/2096-0247.20200038

Video：

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Abstract Full text Figures/Tables Video References Cited by

創傷性腦損傷（Traumatic brain injury，TBI）和癲癇持續狀態（Status epilepticus，SE）皆與人類癲癇的發生發展密切相關。雖病因不同，但目前的研究表明，這些損傷后癲癇發生的分子機制趨于一致。其中一個機制涉及腦源性神經營養因子（Brain-derived neurotrophic factor，BDNF）及其高親和力受體酪氨酸激酶 B（Tropomyosin related kinase B，TrkB）。文章總結了 BDNF / TrkB 信號通路在癲癇發展中所起的病理生理學作用。軸突橫斷模型和 SE 動物模型分別模擬了人類 TBI 和 SE 后誘發的癲癇，在這兩種動物模型的研究基礎上，討論了靶向 BDNF/TrkB 信號通路以減少癲癇發作及其導致的神經損傷的策略。

Citation： 張冉冉, 王珂黙, 石燕婷, 杜倩雯, 劉學伍. 靶向腦源性神經營養因子/酪氨酸激酶 B 信號通路對癲癇的抑制. Journal of Epilepsy, 2020, 6(3): 215-219. doi: 10.7507/2096-0247.20200038 Copy

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2.	Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence ofepilepsy: a systematic review and meta-analysis of international studies. Neurol, 2017, 89(6): 642.
3.	Simonato M, Brooks-Kayal AR, Engel J, et al. The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol, 2014, 13(9): 949-960.
4.	Chen KW, Chen L. Epigenetic regulation of BDNF gene during development and diseases. Int J Mol Sci, 2017, 18(3): 571.
5.	Kramár EA, Chen LY, Lauterborn JC, et al. BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats. Neurobiol Aging, 2012, 33(4): 708-719.
6.	Cook DJ, Nguyen C, Chun, HN, et al. Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke. J Cereb Blood Flow Metab, 2016, 37(3): 1030-1045.
7.	Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia, 2017, 58(Suppl.3): 27-38.
8.	Kelly KM, Miller ER, Lepsveridze E, et al. Posttraumatic seizures and epilepsy in adult rats after controlled cortical impact. Epilepsy Res, 2015, 117: 104-116.
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10.	Ping X, Jin X. Chronic posttraumatic epilepsy following neocortical undercut lesion in mice. PLoS One, 2016, 11(6): e0158231.
11.	Gu F, Parada I, Yang T, et al. Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons. Neurobiol Dis, 2018, 113: 45-58.
12.	Jin X, Prince DA, Huguenard JR. Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epilep togenic neocortex in rats. J Neurosci, 2006, 26(18): 4891-4900.
13.	Gu F, Parada I, Shen F, et al. Structural alterations in fast-spiking GABAergic interneurons in a modelof posttraumatic neocortical epileptogenesis. Neurobiol Dis, 2017, 108: 100-114.
14.	Cembrowski MS, Phillips MG, DiLisio SF, et al. Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes. Cell, 2018, 173: 1280-1292.
15.	Massa SM, Yang T, Xie Y, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest, 2010, 120(5): 1774-1785.
16.	Dinocourt C, Gallagher SE, Thompson SM. Injury-induced axonal sprouting in the hippocampus is initiated by activation of TrkB receptors. Eur J Neurosci, 2006, 24(7): 1857-1866.
17.	Aungst S, England PM, Thompson SM. Critical role of TrkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury. J Neurophysiol, 2013, 109(3): 813-824.
18.	Gill R, Chang PK, Prenosil GA, et al. Blocking brain-derived neurotrophic factor inhibits injury-induced hyper-excitability of hippocampal CA3 neurons. Eur J Neurosci, 2013, 38: 3554-3566.
19.	He XP, Pan E, Sciarretta C, et al. Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis. J Neurosci, 2010, 30(18): 6188-6196.
20.	Liu G, Gu B, He XP, et al. Transient inhibition of TrkB kinaseafter status epilepticus prevents development of temporal lobe epilepsy. Neuron, 2013, 79(1): 31-38.
21.	He XP, Wen R, McNamara JO. Impairment of kindling development in phospholipase Cg1 heterozygous mice. Epilepsia, 2014, 55(3): 456-463.
22.	Gu B, Huang YZ, He XP, et al. A peptide uncoupling BDNF receptor TrkB from phospholipase Cg1 prevents epilepsy induced by status epilepticus. Neuron, 2015, 88(3): 484-491.
23.	Huang YZ, He XP, Krishnamurthy K, et al. TrkB-Shc signaling protects against hippocampal injury following status epilepticus. J Neurosci, 2019, 39(23): 4624-4630.
24.	Kuramoto S, Yasuhara T, Agari T, et al. BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats. Brain Res, 2011, 1368: 281-289.
25.	Sasi M, Vignoli B, Canossa M, et al. Neurobiology of local and intercellular BDNF signaling. Pflugers Arch, 2017, 469(5-6): 611.
26.	Falcicchia C, Paolone G, Emerich DF, et al. Seizure-suppressantand neuroprotective effects of encapsulated BDNF-producing cell in a rat model of temporal lobe epilepsy. Mol Ther Methods Clin Dev, 2018, 9: 211-224.
27.	Iughetti L, Lucaccioni L, Fugetto F, et al. Brain-derived neurotrophic factor and epilepsy: a systematic review. Neuropeptides, 2018, 15(72): 23-29.
28.	Xu B, Michalski B, Racine RJ, et al. The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trkexpression and seizure-related morphological changes. J Neurosci, 2004, 126(3): 521-531.
29.	Nagahara AH, Merrill DA, Coppola G. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med, 2009, 15(3): 331-337.
30.	Obeid M, Rosenberg EC, Klein PM, et al. Lestaurtinib (CEP-701) attenuates "second hit" kainic acid-induced seizures following early life hypoxic seizures. Epilepsy Res, 2014, 108(4): 806-810.

1. Manford M. Recent advances in epilepsy. J Neurol, 2017, 264(8): 1811-1824.
2. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence ofepilepsy: a systematic review and meta-analysis of international studies. Neurol, 2017, 89(6): 642.
3. Simonato M, Brooks-Kayal AR, Engel J, et al. The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol, 2014, 13(9): 949-960.
4. Chen KW, Chen L. Epigenetic regulation of BDNF gene during development and diseases. Int J Mol Sci, 2017, 18(3): 571.
5. Kramár EA, Chen LY, Lauterborn JC, et al. BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats. Neurobiol Aging, 2012, 33(4): 708-719.
6. Cook DJ, Nguyen C, Chun, HN, et al. Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke. J Cereb Blood Flow Metab, 2016, 37(3): 1030-1045.
7. Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia, 2017, 58(Suppl.3): 27-38.
8. Kelly KM, Miller ER, Lepsveridze E, et al. Posttraumatic seizures and epilepsy in adult rats after controlled cortical impact. Epilepsy Res, 2015, 117: 104-116.
9. Keret A, Shweiki M, Bennett-Back O, et al. The clinical characteristics of posttraumatic epilepsy following moderate-tosevere traumatic brain injury in children. Seizure, 2018, 58: 29-34.
10. Ping X, Jin X. Chronic posttraumatic epilepsy following neocortical undercut lesion in mice. PLoS One, 2016, 11(6): e0158231.
11. Gu F, Parada I, Yang T, et al. Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons. Neurobiol Dis, 2018, 113: 45-58.
12. Jin X, Prince DA, Huguenard JR. Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epilep togenic neocortex in rats. J Neurosci, 2006, 26(18): 4891-4900.
13. Gu F, Parada I, Shen F, et al. Structural alterations in fast-spiking GABAergic interneurons in a modelof posttraumatic neocortical epileptogenesis. Neurobiol Dis, 2017, 108: 100-114.
14. Cembrowski MS, Phillips MG, DiLisio SF, et al. Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes. Cell, 2018, 173: 1280-1292.
15. Massa SM, Yang T, Xie Y, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest, 2010, 120(5): 1774-1785.
16. Dinocourt C, Gallagher SE, Thompson SM. Injury-induced axonal sprouting in the hippocampus is initiated by activation of TrkB receptors. Eur J Neurosci, 2006, 24(7): 1857-1866.
17. Aungst S, England PM, Thompson SM. Critical role of TrkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury. J Neurophysiol, 2013, 109(3): 813-824.
18. Gill R, Chang PK, Prenosil GA, et al. Blocking brain-derived neurotrophic factor inhibits injury-induced hyper-excitability of hippocampal CA3 neurons. Eur J Neurosci, 2013, 38: 3554-3566.
19. He XP, Pan E, Sciarretta C, et al. Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis. J Neurosci, 2010, 30(18): 6188-6196.
20. Liu G, Gu B, He XP, et al. Transient inhibition of TrkB kinaseafter status epilepticus prevents development of temporal lobe epilepsy. Neuron, 2013, 79(1): 31-38.
21. He XP, Wen R, McNamara JO. Impairment of kindling development in phospholipase Cg1 heterozygous mice. Epilepsia, 2014, 55(3): 456-463.
22. Gu B, Huang YZ, He XP, et al. A peptide uncoupling BDNF receptor TrkB from phospholipase Cg1 prevents epilepsy induced by status epilepticus. Neuron, 2015, 88(3): 484-491.
23. Huang YZ, He XP, Krishnamurthy K, et al. TrkB-Shc signaling protects against hippocampal injury following status epilepticus. J Neurosci, 2019, 39(23): 4624-4630.
24. Kuramoto S, Yasuhara T, Agari T, et al. BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats. Brain Res, 2011, 1368: 281-289.
25. Sasi M, Vignoli B, Canossa M, et al. Neurobiology of local and intercellular BDNF signaling. Pflugers Arch, 2017, 469(5-6): 611.
26. Falcicchia C, Paolone G, Emerich DF, et al. Seizure-suppressantand neuroprotective effects of encapsulated BDNF-producing cell in a rat model of temporal lobe epilepsy. Mol Ther Methods Clin Dev, 2018, 9: 211-224.
27. Iughetti L, Lucaccioni L, Fugetto F, et al. Brain-derived neurotrophic factor and epilepsy: a systematic review. Neuropeptides, 2018, 15(72): 23-29.
28. Xu B, Michalski B, Racine RJ, et al. The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trkexpression and seizure-related morphological changes. J Neurosci, 2004, 126(3): 521-531.
29. Nagahara AH, Merrill DA, Coppola G. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med, 2009, 15(3): 331-337.
30. Obeid M, Rosenberg EC, Klein PM, et al. Lestaurtinib (CEP-701) attenuates "second hit" kainic acid-induced seizures following early life hypoxic seizures. Epilepsy Res, 2014, 108(4): 806-810.

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靶向腦源性神經營養因子/酪氨酸激酶 B 信號通路對癲癇的抑制

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