Research progress on the involvement of neuroinflammation in the occurrence and development of genetic developmental and epileptic encephalopathy_Journal of Epilepsy

Authors：

 HU Chunhui , HUANG Danmei

Department of Neurology, Fujian Children's Hospital, Fuzhou 350014, China;

Corresponding author：

HU Chunhui, Email: huchunhui1989@126.com

Keywords：

Developmental and epileptic encephalopathy; Neuroinflammation; Astrocyte activation

DOI：

10.7507/2096-0247.202504017

Video：

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Abstract Full text Figures/Tables Video References Cited by

Developmental and epileptic encephalopathy (DEE) is a genetic neurological disease affecting 0.27–0.54 per 1000 newborns, with a strong genetic association. Currently, the majority of known pathogenic genes in genetic DEE can be classified into six functional categories: ion channels, organelles and cell membranes, growth and development, synaptic function, neurotransmitters and receptors, DNA and RNA regulation, and signal transduction pathways. Emerging evidence suggests that inflammatory regulation may play a critical role in genetic DEE pathogenesis. Specifically, astrocyte and microglial activation contributes to neuroinflammation in genetic DEE, while pro-inflammatory cytokines disrupt neuron-glia interactions, exacerbating epileptic seizures and neuronal damage. Targeting the source mechanism of neuroinflammation in genetic DEE, such as the activation of astrocytes and microglia, and intervening from the source, is expected to be a new target for the treatment of genetic DEE.

Citation： HU Chunhui, HUANG Danmei. Research progress on the involvement of neuroinflammation in the occurrence and development of genetic developmental and epileptic encephalopathy. Journal of Epilepsy, 2025, 11(4): 324-330. doi: 10.7507/2096-0247.202504017 Copy

1.	Specchio N, Trivisano M, Aronica E, et al. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. Lancet Child Adolesc Health, 2024, 8(11): 821-834.
2.	Palmer EE, Howell K, Scheffer IE. Natural history studies and clinical trial readiness for genetic developmental and epileptic encephalopathies. Neurotherapeutics, 2021, 18(3): 1432-1444.
3.	Kaplan DI, Isom LL, Petrou S. Role of sodium channels in epilepsy. Cold Spring Harbor Perspectives in Medicine, 2016, 6(6): a022814.
4.	Hu C, Liu D, Wang H. Col4a2 mutations contribute to infantile epileptic spasm syndrome and neuroinflammation. Int J Med Sci, 2024, 21(9): 1756-1768.
5.	Terrone G, Balosso S, Pauletti A, et al. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology, 2020, 167: 107742.
6.	Granata T, Fusco L, Matricardi S, et al. Inflammation in pediatric epilepsies: update on clinical features and treatment options. Epilepsy Behav, 2021, 17: 107959.
7.	McElroy PB, Liang LP, Day BJ, et al. Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Exp Neurol, 2017, 298(Pt A): 13-22.
8.	Barker-Haliski ML, Löscher W, White HS, et al. Neuroinflammation in epileptogenesis: insights and translational perspectives from new models of epilepsy. Epilepsia, 2017, 58(Suppl 3): 39-47.
9.	Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol, 2019, 15(8): 459-472.
10.	Orsini A, Foiadelli T, Costagliola G, et al. The role of inflammatory mediators in epilepsy Focus on developmental and epileptic encephalopathies and therapeutic implications. Epilepsy Res, 2021, 172: 106588.
11.	Tomasoni R, Morini R, Lopez-Atalaya JP, et al. Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects. Elife, 2017, 6: e21735.
12.	Pozzi D, Menna E, Canzi A, et al. The communication between the immune and nervous systems: the role of IL-1β in synaptopathies. Front Mol Neurosci, 2018, 11: 111.
13.	Yang CC, Lin CC, Jou MJ, et al. RTA 408 inhibits interleukin-1β-induced MMP-9 expression via suppressing protein kinase-dependent NF-κB and AP-1 activation in rat brain astrocytes. Int J Mol Sci, 2019, 20(11): 2826.
14.	Kaila K, Price TJ, Payne JA, et al. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci, 2014, 15(10): 637-654.
15.	Pecorelli A, Cordone V, Messano N, et al. Altered inflammasome machinery as a key player in the perpetuation of Rett syndrome oxinflammation. Redox Biol, 2020, 28: 101334.
16.	Pecorelli A, Cervellati C, Cordone V, et al. Compromised immune/inflammatory responses in Rett syndrome. Free Radic Biol Med, 2020, 152: 100-106.
17.	Corradini I, Focchi E, Rasile M, et al. Maternal immune activation delays excitatory-to-inhibitory gamma-aminobutyric acid switch in offspring. Biol Psychiatry, 2018, 83(8): 680-691.
18.	Higurashi N, Takahashi Y, Kashimada A, et al. Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy. Seizure, 2015, 27: 1-5.
19.	Trivisano M, Lucchi C, Rustichelli C, et al. Reduced steroidogenesis in patients with PCDH19-female limited epilepsy. Epilepsia, 2017, 58(6): e91-e95.
20.	Varughese RT, Karkare S, Poduri A, et al. Child neurology initial presentation of PCDH19-related epilepsy with new-onset refractory status epilepticus and treatment with anakinra. Neurology, 2022, 99(5): 208-211.
21.	Marini C, Porro A, Rastetter A, et al. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain, 2018, 141(11): 3160-3178.
22.	Magri S, Taroni F, Costa C, et al. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature. Epilepsy Res, 2019, 153: 49-58.
23.	Frigerio F, Flynn C, Han Y, et al. Neuroinflammation alters integrative properties of rat hippocampal pyramidal cells. Mol Neurobiol, 2018, 55(9): 7500-7511.
24.	Shen W, Poliquin S, Macdonald RL, et al. Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2 +/Q390X knockin: a link between genetic and acquired epilepsy? Epilepsia, 2020, 61(10): 2301-2312.
25.	Cortelazzo A, de Felice C, Leoncini S, et al. Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation. Inflamm Res, 2017, 66(3): 269-280.
26.	Galvani G, Mottolese N, Gennaccaro L, et al. Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder. J Neuroinflammation, 2021, 18(1): 155.
27.	Tassinari M, Mottolese N, Galvani G, et al. Luteolin treatment ameliorates brain development and behavioral performance in a mouse model of CDKL5 deficiency disorder. Int J Mol Sci, 2022, 23(15): 8719.
28.	Tapella L, Dematteis G, Ruffinatti FA, et al. Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures. Cell Calcium, 2021, 100: 102480.
29.	Gruber VE, Luinenburg MJ, Colleselli K, et al. Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions. Epilepsia, 2022, 63(2): 364-374.
30.	Kumamoto T, Tsurugizawa T. Potential of multiscale astrocyte imaging for revealing mechanisms underlying neurodevelopmental disorders. Int J Mol Sci, 2021, 22: 10312.
31.	Binder DK, Steinhäuser C. Astrocytes and epilepsy. Neurochem Res, 2021, 46(10): 2687-2695.
32.	Lezmy J, Arancibia-Cárcamo IL, Quintela-López T, et al. Astrocyte Ca(2+)-evoked ATP release regulates myelinated axon excitability and conduction speed. Science, 2021, 374(6565): eabh2858.
33.	Farina MG, Sandhu MRS, Parent M, et al. Small loci of astroglial glutamine synthetase deficiency in the postnatal brain cause epileptic seizures and impaired functional connectivity. Epilepsia, 2021, 62(11): 2858-2870.
34.	Thompson JA, Miralles RM, Wengert ER, et al. Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy. Epilepsia Open, 2022, 7(2): 280-292.
35.	Goisis RC, Chiavegato A, Gomez-Gonzalo M, et al. GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome. Front Cell Neurosci, 2022, 16: 919493.
36.	Peterson AR, Garcia TA, Cullion K, et al. Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy. Neurobiol Dis, 2021, 157: 105443.
37.	Lentini C, d'Orange M, Marichal N, et al. Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell, 2021, 28(12): 2104-2121. e10.
38.	Tavassoli Z, Giahi M, Janahmadi M, et al. Glial cells inhibition affects the incidence of metaplasticity in the hippocampus of Pentylentetrazole-induced kindled rats. Epilepsy Behav, 2022, 135: 108907.
39.	Ammothumkandy A, Ravina K, Wolseley V, et al. Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy. Nat Neurosci, 2022, 25(4): 493-503.
40.	Vezzani A, Ravizza T, Bedner P, et al. Astrocytes in the initiation and progression of epilepsy. Nat Rev Neurol, 2022, 18(12): 707-722.

1. Specchio N, Trivisano M, Aronica E, et al. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives. Lancet Child Adolesc Health, 2024, 8(11): 821-834.
2. Palmer EE, Howell K, Scheffer IE. Natural history studies and clinical trial readiness for genetic developmental and epileptic encephalopathies. Neurotherapeutics, 2021, 18(3): 1432-1444.
3. Kaplan DI, Isom LL, Petrou S. Role of sodium channels in epilepsy. Cold Spring Harbor Perspectives in Medicine, 2016, 6(6): a022814.
4. Hu C, Liu D, Wang H. Col4a2 mutations contribute to infantile epileptic spasm syndrome and neuroinflammation. Int J Med Sci, 2024, 21(9): 1756-1768.
5. Terrone G, Balosso S, Pauletti A, et al. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology, 2020, 167: 107742.
6. Granata T, Fusco L, Matricardi S, et al. Inflammation in pediatric epilepsies: update on clinical features and treatment options. Epilepsy Behav, 2021, 17: 107959.
7. McElroy PB, Liang LP, Day BJ, et al. Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Exp Neurol, 2017, 298(Pt A): 13-22.
8. Barker-Haliski ML, Löscher W, White HS, et al. Neuroinflammation in epileptogenesis: insights and translational perspectives from new models of epilepsy. Epilepsia, 2017, 58(Suppl 3): 39-47.
9. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol, 2019, 15(8): 459-472.
10. Orsini A, Foiadelli T, Costagliola G, et al. The role of inflammatory mediators in epilepsy Focus on developmental and epileptic encephalopathies and therapeutic implications. Epilepsy Res, 2021, 172: 106588.
11. Tomasoni R, Morini R, Lopez-Atalaya JP, et al. Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects. Elife, 2017, 6: e21735.
12. Pozzi D, Menna E, Canzi A, et al. The communication between the immune and nervous systems: the role of IL-1β in synaptopathies. Front Mol Neurosci, 2018, 11: 111.
13. Yang CC, Lin CC, Jou MJ, et al. RTA 408 inhibits interleukin-1β-induced MMP-9 expression via suppressing protein kinase-dependent NF-κB and AP-1 activation in rat brain astrocytes. Int J Mol Sci, 2019, 20(11): 2826.
14. Kaila K, Price TJ, Payne JA, et al. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci, 2014, 15(10): 637-654.
15. Pecorelli A, Cordone V, Messano N, et al. Altered inflammasome machinery as a key player in the perpetuation of Rett syndrome oxinflammation. Redox Biol, 2020, 28: 101334.
16. Pecorelli A, Cervellati C, Cordone V, et al. Compromised immune/inflammatory responses in Rett syndrome. Free Radic Biol Med, 2020, 152: 100-106.
17. Corradini I, Focchi E, Rasile M, et al. Maternal immune activation delays excitatory-to-inhibitory gamma-aminobutyric acid switch in offspring. Biol Psychiatry, 2018, 83(8): 680-691.
18. Higurashi N, Takahashi Y, Kashimada A, et al. Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy. Seizure, 2015, 27: 1-5.
19. Trivisano M, Lucchi C, Rustichelli C, et al. Reduced steroidogenesis in patients with PCDH19-female limited epilepsy. Epilepsia, 2017, 58(6): e91-e95.
20. Varughese RT, Karkare S, Poduri A, et al. Child neurology initial presentation of PCDH19-related epilepsy with new-onset refractory status epilepticus and treatment with anakinra. Neurology, 2022, 99(5): 208-211.
21. Marini C, Porro A, Rastetter A, et al. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain, 2018, 141(11): 3160-3178.
22. Magri S, Taroni F, Costa C, et al. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature. Epilepsy Res, 2019, 153: 49-58.
23. Frigerio F, Flynn C, Han Y, et al. Neuroinflammation alters integrative properties of rat hippocampal pyramidal cells. Mol Neurobiol, 2018, 55(9): 7500-7511.
24. Shen W, Poliquin S, Macdonald RL, et al. Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2 +/Q390X knockin: a link between genetic and acquired epilepsy? Epilepsia, 2020, 61(10): 2301-2312.
25. Cortelazzo A, de Felice C, Leoncini S, et al. Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation. Inflamm Res, 2017, 66(3): 269-280.
26. Galvani G, Mottolese N, Gennaccaro L, et al. Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder. J Neuroinflammation, 2021, 18(1): 155.
27. Tassinari M, Mottolese N, Galvani G, et al. Luteolin treatment ameliorates brain development and behavioral performance in a mouse model of CDKL5 deficiency disorder. Int J Mol Sci, 2022, 23(15): 8719.
28. Tapella L, Dematteis G, Ruffinatti FA, et al. Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures. Cell Calcium, 2021, 100: 102480.
29. Gruber VE, Luinenburg MJ, Colleselli K, et al. Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions. Epilepsia, 2022, 63(2): 364-374.
30. Kumamoto T, Tsurugizawa T. Potential of multiscale astrocyte imaging for revealing mechanisms underlying neurodevelopmental disorders. Int J Mol Sci, 2021, 22: 10312.
31. Binder DK, Steinhäuser C. Astrocytes and epilepsy. Neurochem Res, 2021, 46(10): 2687-2695.
32. Lezmy J, Arancibia-Cárcamo IL, Quintela-López T, et al. Astrocyte Ca(2+)-evoked ATP release regulates myelinated axon excitability and conduction speed. Science, 2021, 374(6565): eabh2858.
33. Farina MG, Sandhu MRS, Parent M, et al. Small loci of astroglial glutamine synthetase deficiency in the postnatal brain cause epileptic seizures and impaired functional connectivity. Epilepsia, 2021, 62(11): 2858-2870.
34. Thompson JA, Miralles RM, Wengert ER, et al. Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy. Epilepsia Open, 2022, 7(2): 280-292.
35. Goisis RC, Chiavegato A, Gomez-Gonzalo M, et al. GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome. Front Cell Neurosci, 2022, 16: 919493.
36. Peterson AR, Garcia TA, Cullion K, et al. Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy. Neurobiol Dis, 2021, 157: 105443.
37. Lentini C, d'Orange M, Marichal N, et al. Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell, 2021, 28(12): 2104-2121. e10.
38. Tavassoli Z, Giahi M, Janahmadi M, et al. Glial cells inhibition affects the incidence of metaplasticity in the hippocampus of Pentylentetrazole-induced kindled rats. Epilepsy Behav, 2022, 135: 108907.
39. Ammothumkandy A, Ravina K, Wolseley V, et al. Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy. Nat Neurosci, 2022, 25(4): 493-503.
40. Vezzani A, Ravizza T, Bedner P, et al. Astrocytes in the initiation and progression of epilepsy. Nat Rev Neurol, 2022, 18(12): 707-722.

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