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

Nature Reviews Neuroscience volume 25, pages 334–350 (2024)Cite this article

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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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Fig. 1: Overview of the mTOR pathway and the consequences of its hyperactivation for epileptogenesis.
Fig. 2: Interactions between mTOR and neuroinflammation in structural epilepsies.

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Acknowledgements

The authors are grateful to S. Garattini for his insightful comments on the initial version of the article. The authors acknowledge funding which supported studies relevant for this publication: The Netherlands Organization for Health Research and Development (ZonMw; project 09120012010007; E.A.), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 952455 (EpiEpiNet; E.A.) and Fondazione Italo Monzino (Milano; A.V.).

Author information

Author notes

  1. These authors contributed equally: Teresa Ravizza, Mirte Scheper.

Authors and Affiliations

  1. Department of Acute Brain and Cardiovascular Injury, Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy

    Teresa Ravizza, Rossella Di Sapia & Annamaria Vezzani

  2. Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Mirte Scheper & Eleonora Aronica

  3. Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands

    Jan Gorter

  4. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands

    Eleonora Aronica

Authors
  1. Teresa Ravizza
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  2. Mirte Scheper
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  3. Rossella Di Sapia
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  4. Jan Gorter
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  5. Eleonora Aronica
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  6. Annamaria Vezzani
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Contributions

All authors researched data for, and contributed to the writing of, the article. A.V., T.R., J.G. and E.A. made substantial contribution to discussions of the content. A.V., J.G. and E.A. reviewed and edited the manuscript before submission.

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Correspondence to Eleonora Aronica or Annamaria Vezzani.

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Nature Reviews Neuroscience thanks Detlev Boison and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Ravizza, T., Scheper, M., Di Sapia, R. et al. mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment. Nat. Rev. Neurosci. 25, 334–350 (2024). https://doi.org/10.1038/s41583-024-00805-1

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