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Krüppel-like factors: potential roles in blood-brain barrier dysfunction and epileptogenesis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Epilepsy is a chronic and debilitating neurological disorder, known for the occurrence of spontaneous and recurrent seizures. Despite the availability of antiseizure drugs, 30% of people with epilepsy experience uncontrolled seizures and drug resistance, evidencing that new therapeutic options are required. The process of epileptogenesis involves the development and expansion of tissue capable of generating spontaneous recurrent seizures, during which numerous events take place, namely blood-brain barrier (BBB) dysfunction, and neuroinflammation. The consequent cerebrovascular dysfunction results in a lower seizure threshold, seizure recurrence, and chronic epilepsy. This suggests that improving cerebrovascular health may interrupt the pathological cycle responsible for disease development and progression. Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors, encountered in brain endothelial cells, glial cells, and neurons. KLFs are known to regulate vascular function and changes in their expression are associated with neuroinflammation and human diseases, including epilepsy. Hence, KLFs have demonstrated various roles in cerebrovascular dysfunction and epileptogenesis. This review critically discusses the purpose of KLFs in epileptogenic mechanisms and BBB dysfunction, as well as the potential of their pharmacological modulation as therapeutic approach for epilepsy treatment.

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Fig. 1: Main events of epileptogenesis.
Fig. 2: Healthy blood-brain barrier (BBB) versus damaged BBB in epilepsy.
Fig. 3: Krüppel-like factors (KLFs) structure and involvement in inflammation through transcriptional activation.
Fig. 4: Repressor element-1 silencing transcription factor (REST) structure and function as transcriptional repressor.
Fig. 5: Krüppel-like factor (KLF) modulation as potential therapeutic approach in epilepsy.

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Acknowledgements

The authors acknowledge Fundo Europeu de Desenvolvimento Regional (FEDER) through Portugal2020 in the scope of the Operational Programme for Competitiveness and Internationalization; Fundação para a Ciência e Tecnologia (FCT), Portuguese Agency for Scientific Research, within the scope of the research project 2022.03133.PTDC and Ph.D. research grant 2021.06125.BD; Spanish Ministerio de Ciencia e Innovación (PID2021-123462OB-I00); the Generalitat de Catalunya (2021 SGR 00288); CIBERNED (Grant CB06/05/2004); and Institut de Neurociències UB, (CEX2021-001159-M). ME is Serra Hunter fellow.

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Authors and Affiliations

  1. University of Coimbra, Faculty of Pharmacy, Coimbra, Portugal

    Ana Beatriz Santos, Andreia Carona, Amílcar Falcão, Ana Fortuna & Joana Bicker

  2. University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research, Coimbra, Portugal

    Andreia Carona, Amílcar Falcão, Ana Fortuna & Joana Bicker

  3. Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    Miren Ettcheto & Antoni Camins

  4. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain

    Miren Ettcheto & Antoni Camins

  5. Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain

    Miren Ettcheto & Antoni Camins

  6. Institut d’Investigació Sanitària Pere Virgili (IISPV), Reus, Spain

    Miren Ettcheto & Antoni Camins

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  1. Ana Beatriz Santos
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  2. Andreia Carona
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  3. Miren Ettcheto
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  4. Antoni Camins
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  5. Amílcar Falcão
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  6. Ana Fortuna
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  7. Joana Bicker
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Contributions

Ana Beatriz Santos: Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft, Writing—review & editing; Andreia Carona: Formal analysis, Writing—original draft, Writing—review & editing; Miren Ettcheto: Formal analysis, Writing—review & editing; Antoni Camins: Formal analysis, Writing—review & editing; Amílcar Falcão: Formal analysis, Writing—review & editing; Ana Fortuna: Data curation, Formal analysis, Writing—original draft, Writing—review & editing; Joana Bicker: Conceptualization; Formal analysis, Writing—original draft, Writing—review & editing; Funding acquisition.

Corresponding author

Correspondence to Joana Bicker.

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Santos, A.B., Carona, A., Ettcheto, M. et al. Krüppel-like factors: potential roles in blood-brain barrier dysfunction and epileptogenesis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01285-w

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