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Cited by 141Epilepsy research and treatmentNeuroscience and Neuropharmacology ResearchTuberous Sclerosis Complex Research

mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment

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Ravizza, Teresa, Scheper, Mirte, Di Sapia, Rossella, Gorter, Jan, Aronica, Eleonora, Vezzani, Annamaria·2024·Nature Reviews Neuroscience
DOI 10.1038/s41583-024-00805-1
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Abstract

Epilepsy remains a major health concern as anti-seizure medications frequently fail, and there is currently no treatment to stop or prevent epileptogenesis, the process underlying the onset and progression of epilepsy. The identification of the pathological processes underlying epileptogenesis is instrumental to the development of drugs that may prevent the generation of seizures or control pharmaco-resistant seizures, which affect about 30% of patients. mTOR signalling and neuroinflammation have been recognized as critical pathways that are activated in brain cells in epilepsy. They represent a potential node of biological convergence in structural epilepsies with either a genetic or an acquired aetiology. Interventional studies in animal models and clinical studies give strong support to the involvement of each pathway in epilepsy. In this Review, we focus on available knowledge about the pathophysiological features of mTOR signalling and the neuroinflammatory brain response, and their interactions, in epilepsy. We discuss mitigation strategies for each pathway that display therapeutic effects in experimental and clinical epilepsy. A deeper understanding of these interconnected molecular cascades could enhance our strategies for managing epilepsy. This could pave the way for new treatments to fill the gaps in the development of preventative or disease-modifying drugs, thus overcoming the limitations of current symptomatic medications.

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  • Astrocytes can gain neurotoxic functions, such as the secretion of inflammatory cytokines, as observed in TSC2−/− organoids.

    “Astrocytes can also gain neurotoxic functions, such as the secretion of inflammatory cytokines53, as observed in TSC2−/− organoids.”

    From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [53]

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References 236 · Cited by 141

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  1. Chen, Z., Brodie, M. J., Ding, D. & Kwan, P. Editorial: epidemiology of epilepsy and seizures. Front. Epidemiol. 3, 1273163 (2023).
  2. Devinsky, O. et al. Epilepsy. Nat. Rev. Dis. Prim. 4, 18024 (2018).
  3. Pitkanen, A., Lukasiuk, K., Dudek, F. E. & Staley, K. J. Epileptogenesis. Cold Spring Harb. Perspect. Med. 5, a022822 (2015).
  4. Galanopoulou, A. S. et al. Antiepileptogenesis and disease modification: progress, challenges, and the path forward -Report of the Preclinical Working Group of the 2018 NINDS-sponsored antiepileptogenesis and disease modification workshop. Epilepsia Open 6, 276-296 (2021).
  5. Vezzani, A., Balosso, S. & Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat. Rev. Neurol. 15, 459-472 (2019). This review describes inflammatory pathways that are activated in pharmaco-resistant epilepsy and can be modulated in animal models to produce therapeutic effects.
  6. Aronica, E., Specchio, N., Luinenburg, M. J. & Curatolo, P. Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy. Brain 146, 2694-2710 (2023). This review provides an overview of the different biological mechanisms throughout the life course, even beyond the epileptogenic process, in individuals with tuberous sclerosis complex.
  7. Girodengo, M., Ultanir, S. K. & Bateman, J. M. Mechanistic target of rapamycin signaling in human nervous system development and disease. Front. Mol. Neurosci. 15, 1005631 (2022).
  8. Andrews, M. G., Subramanian, L. & Kriegstein, A. R. mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex. eLife 9, e58737 (2020).
  9. Gerasimenko, A., Baldassari, S. & Baulac, S. mTOR pathway: insights into an established pathway for brain mosaicism in epilepsy. Neurobiol. Dis. 182, 106144 (2023).
  10. Okoh, J. et al. Targeted suppression of mTORC2 reduces seizures across models of epilepsy. Nat. Commun. 14, 7364 (2023).
  11. Hodges, S. L. & Lugo, J. N. Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy. Epilepsy Res. 161, 106282 (2020).
  12. Fernandes, S. A. & Demetriades, C. The multifaceted role of nutrient sensing and mTORC1 signaling in physiology and aging. Front Aging 2, 707372 (2021).
  13. Nguyen, L. H. & Bordey, A. Current review in basic science: animal models of focal cortical dysplasia and epilepsy. Epilepsy Curr. 22, 234-240 (2022).
  14. Moavero, R. et al. Genetic pathogenesis of the epileptogenic lesions in tuberous sclerosis complex: therapeutic targeting of the mTOR pathway. Epilepsy Behav. 131, 107713 (2022).
  15. Guo, D., Zeng, L., Brody, D. L. & Wong, M. Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS ONE 8, e64078 (2013). This study provides evidence that rapamycin treatment for 1 month after traumatic brain injury decreased the seizure frequency and rate of developing post-traumatic epilepsy, showing inhibition of epileptogenesis.
  16. Koike-Kumagai, M., Fujimoto, M. & Wataya-Kaneda, M. Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice. Neuropharmacology 218, 109203 (2022).
  17. Petrasek, T. et al. mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus. J. Neurodev. Disord. 13, 14 (2021).
  18. Drion, C. M. et al. Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo -in search of potential anti-epileptogenic strategies for temporal lobe epilepsy. J. Neuroinflammation 15, 212 (2018). This study shows that rapamycin in the post-status epilepticus rat model neither suppressed the expression of inflammatory and oxidative stress markers in bulk tissue nor reduced the levels of IL-6 and COX2 in cultured astrocytes challenged with IL-1β.
  19. Saffari, A. et al. Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age -a multicenter retrospective study. Orphanet J. Rare Dis. 14, 96 (2019).
  20. Leitner, D. F. et al. Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia. PLoS ONE 17, e0268597 (2022).
  21. Vezzani, A., Lang, B. & Aronica, E. Immunity and inflammation in epilepsy. Cold Spring Harb. Perspect. Med. 6, a022699 (2015).
  22. Sharma, R. et al. Neuroinflammation in post-traumatic epilepsy: pathophysiology and tractable therapeutic targets. Brain Sci. 9, 318 (2019).
  23. Mills, J. D. et al. Coding and non-coding transcriptome of mesial temporal lobe epilepsy: critical role of small non-coding RNAs. Neurobiol. Dis. 134, 104612 (2020).
  24. Kan, A. A. et al. Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines. J. Neuroinflammation 9, 207 (2012).
  25. Pohlentz, M. S. et al. Characterisation of NLRP3 pathway-related neuroinflammation in temporal lobe epilepsy. PLoS ONE 17, e0271995 (2022).
  26. Gelot, A. B. & Represa, A. Progression of fetal brain lesions in tuberous sclerosis complex. Front. Neurosci. 14, 899 (2020).
  27. van Vliet, E. A., Aronica, E., Vezzani, A. & Ravizza, T. Review: neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol. Appl. Neurobiol. 44, 91-111 (2018).
  28. Vezzani, A., Di Sapia, R., Kebede, V., Balosso, S. & Ravizza, T. Neuroimmunology of status epilepticus. Epilepsy Behav. 140, 109095 (2023).
  29. Paladini, M. S., Feng, X., Krukowski, K. & Rosi, S. Microglia depletion and cognitive functions after brain injury: from trauma to galactic cosmic ray. Neurosci. Lett. 741, 135462 (2021). 112. Vincent, A., Irani, S. R. & Lang, B. The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. Curr. Opin. Neurol. 23, 144-150 (2010). 113. Tan, T. H.-L., Perucca, P., O'Brien, T. J., Kwan, P. & Monif, M. Inflammation, ictogenesis, and epileptogenesis: an exploration through human disease. Epilepsia 62, 303-324 (2021). 114. Zhang, X. et al. Glucocorticoid receptors participate in epilepsy in FCDII patients and MP model rats: a potential therapeutic target for epilepsy in patients with focal cortical dysplasia II (FCDII). Exp. Opin. Ther. Targets 26, 171-186 (2022). 115. Brunson, K. L., Avishai-Eliner, S. & Baram, T. Z. ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability. Int. Rev. Neurobiol. 49, 185-197 (2002). 116. Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324-337 (2009). 117. Kato, H. & Perl, A. Roles of mechanistic target of rapamycin in the adaptive and innate immune systems. in Molecules to Medicine with mTOR (Elsevier, 2016). 118.
  30. Maldonado, M. et al. Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol. Dis. 14, 279-290 (2003). 135. Zurolo, E. et al. Activation of TLR, RAGE and HMGB1 signaling in malformations of cortical development. Brain 134, 1015-1032 (2011). 136. Jansen, L. A., Uhlmann, E. J., Crino, P. B., Gutmann, D. H. & Wong, M. Epileptogenesis and reduced inward rectifier potassium current in tuberous sclerosis complex-1-deficient astrocytes. Epilepsia 46, 1871-1880 (2005). 137. Zhang, B., Zou, J., Rensing, N. R., Yang, M. & Wong, M. Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol. Dis. 80, 70-79 (2015). 138. Zimmer, T. S. et al. Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations. Neuropathol. Appl. Neurobiol. 46, 546-563 (2020). 139. Lisi, L., Navarra, P., Feinstein, D. L. & Dello Russo, C. The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes. J. Neuroinflammation 8, 1 (2011). 140. Zeng, C., Hu, J., Chen, F., Huang, T. & Zhang, L. The coordination of mTOR signaling and non-coding RNA in regulating epileptic neuroinflammation. Front. Immunol. 13, 924642 (2022). 141. Nguyen, L. H. & Bordey, A. Convergent and divergent mechanisms of epileptogenesis in mTORopathies. Front. Neuroanat. 15, 664695 (2021). 142. Koene, L. M. et al. Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis. JCI Insight 6, e150120 (2021). 143. Koene, L. M. C. et al. Effects of antiepileptic drugs in a new TSC/mTOR-dependent epilepsy mouse model. Ann. Clin. Transl. Neurol. 6, 1273-1291 (2019). 144. Lozovaya, N. et al. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat. Commun. 5, 4563 (2014). This study shows that NMDA receptors are candidates to explain the hyperexcitability of tuberous sclerosis complex neuronal networks. Data suggest that GluN2C subunit upregulation is of key importance in the manifestation of epileptic phenotypes associated with tuberous sclerosis complex. 145.
  31. Galic, M. A., Riazi, K. & Pittman, Q. J. Cytokines and brain excitability. Front. Neuroendocrinol. 33, 116-125 (2012). 163. Villasana-Salazar, B. & Vezzani, A. Neuroinflammation microenvironment sharpens seizure circuit. Neurobiol. Dis. 178, 106027 (2023). 164. Badimon, A. et al. Negative feedback control of neuronal activity by microglia. Nature 586, 417-423 (2020). 165. Hu, Y. et al. Microglia sense and suppress epileptic neuronal hyperexcitability. Pharmacol. Res. 195, 106881 (2023). 166. Patel, D. C., Tewari, B. P., Chaunsali, L. & Sontheimer, H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat. Rev. Neurosci. 20, 282-297 (2019). 167. Wan, Y. et al. Microglial displacement of GABAergic synapses is a protective event during complex febrile seizures. Cell Rep. 33, 108346 (2020). 168.
  32. Johnson, H. L., Jin, F., Pirko, I. & Johnson, A. J. Theiler's murine encephalomyelitis virus as an experimental model system to study the mechanism of blood-brain barrier disruption. J. Neurovirol. 20, 107-112 (2014). 194. Klement, W. et al. Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol. Dis. 113, 70-81 (2018). 195. Gruber, V.-E. et al. Impaired myelin production due to an intrinsic failure of oligodendrocytes in mTORpathies. Neuropathol. Appl. Neurobiol. 47, 812-825 (2021). 196. Mühlebner, A. et al. Myelin pathology beyond white matter in tuberous sclerosis complex (TSC) cortical tubers. J. Neuropathol. Exp. Neurol. 79, 1054-1064 (2020). 197. Merson, T. D., Binder, M. D. & Kilpatrick, T. J. Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular Med. 12, 99-132 (2010). 198. Song, S. et al. Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury. J. Neuroinflammation 19, 246 (2022). 199. de Curtis, M., Garbelli, R. & Uva, L. A hypothesis for the role of axon demyelination in seizure generation. Epilepsia 62, 583-595 (2021). 200. Limanaqi, F. et al. mTOR-related cell-clearing systems in epileptic seizures, an update. Int. J. Mol. Sci. 21, 1642 (2020). 201. Chen, Y., Chen, J., Xing, Z., Peng, C. & Li, D. Autophagy in neuroinflammation: a focus on epigenetic regulation. Aging Dis. https://doi.org/10.14336/AD.2023.0718-1 (2023). 202. Muller, S. et al. Autophagy in neuroinflammatory diseases. Autoimmun. Rev. 16, 856-874 (2017). 203. Jin, M.-M. et al. A critical role of autophagy in regulating microglia polarization in neurodegeneration. Front. Aging Neurosci. 10, 378 (2018). 204. · DOI
  33. Lei, C., Li, Y., Zhu, X., Li, H. & Chang, X. HMGB1/TLR4 induces autophagy and promotes neuroinflammation after intracerebral hemorrhage. Brain Res. 1792, 148003 (2022). 205. Broekaart, D. W. M. et al. Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway. Epilepsia 58, 1462-1472 (2017). 206. Mishto, M. et al. The immunoproteasome Beta5i subunit is key contributor to ictogenesis in a rat model of chronic epilepsy. Brain Behav. Immun. 49, 188-196 (2015). 207.
  34. Ferrington, D. A. & Gregerson, D. S. Immunoproteasomes: structure, function, and antigen presentation. Prog. Mol. Biol. Transl. Sci. 109, 75-112 (2012). 208. van Scheppingen, J. et al. Dysregulation of the (immuno)proteasome pathway in malformations of cortical development. J. Neuroinflammation 13, 202 (2016). 209. Tomimatsu, K. & Narita, M. Translating the effects of mTOR on secretory senescence. Nat. Cell Biol. 17, 1230-1232 (2015). 210. Kumari, R. & Jat, P. Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front. Cell Dev. Biol. 9, 645593 (2021). 211.
  35. Clarkson, B. D. S. et al. Functional deficiency in endogenous interleukin-1 receptor antagonist in patients with febrile infection-related epilepsy syndrome. Ann. Neurol. 85, 526-537 (2019). 224. Pollard, J. R. et al. The TARC/sICAM5 ratio in patient plasma is a candidate biomarker for drug resistant epilepsy. Front. Neurol. 3, 181 (2013). 225. Sun, F.-J. et al. Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex. J. Neuroinflammation 13, 85 (2016). 226. Frigerio, F. et al. n-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain 141, 3130-3143 (2018). 227. Pernhorst, K. et al. TLR4, ATF-3 and IL8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue. Seizure 22, 675-678 (2013). 228. Brennan, G. P. & Henshall, D. C. MicroRNAs as regulators of brain function and targets for treatment of epilepsy. Nat. Rev. Neurol. 16, 506-519 (2020). 229. Fuso, A. et al. Promoter-specific hypomethylation correlates with IL-1β overexpression in tuberous sclerosis complex (TSC). J. Mol. Neurosci. 59, 464-470 (2016).

Authors
Ravizza, T., Scheper, M., Di Sapia, R., Gorter, J., Aronica, E., & Vezzani, A.
Affiliations
  • Mario Negri Institute for Pharmacological Research (IT)
  • Amsterdam University Medical Centers (NL)
  • University of Amsterdam (NL)
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2024-03-26
Volume
25
Issue
5
Pages
334-350
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-024-00805-1
OpenAlex
W4393180863
Cited by
141
References
236
Citations by year
2026: 56 · 2025: 63 · 2024: 22
FWCI
12.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (submittedVersion, other-oa)
Funders
  • European Commission (952455, HORIZON2020)
  • ZonMw (09120012010007)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
Keywords
mTOR signaling, neuroinflammation, epilepsy, epileptogenesis, drug-resistant epilepsy, structural epilepsy, mTOR inhibitors, disease-modifying therapy, antiepileptic drugs, therapeutic target
MeSH terms
Neuroinflammatory Diseases, Animals, Anticonvulsants, Brain, Epilepsy, Humans, Signal Transduction, Disease Progression, TOR Serine-Threonine Kinases

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