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Enhancing glymphatic fluid transport by pan-adrenergic inhibition suppresses epileptogenesis in male mice

Author

Listed:
  • Qian Sun

    (University of Rochester
    Fudan University)

  • Sisi Peng

    (University of Rochester
    Shanghai Universal Medical Imaging Diagnostic Center)

  • Qiwu Xu

    (University of Rochester)

  • Pia Weikop

    (University of Copenhagen Faculty of Health and Medical Sciences)

  • Rashad Hussain

    (University of Rochester)

  • Wei Song

    (University of Rochester)

  • Maiken Nedergaard

    (University of Rochester
    University of Copenhagen Faculty of Health and Medical Sciences)

  • Fengfei Ding

    (University of Rochester
    Fudan University)

Abstract

Epileptogenesis is the process whereby the previously normally functioning brain begins to generate spontaneous, unprovoked seizures. Status epilepticus (SE), which entails a massive release of neuronal glutamate and other neuroactive substances, is one of the best-known triggers of epileptogenesis. We here asked whether pharmacologically promoting glymphatic clearance during or after SE is beneficial and able to attenuate the subsequent epileptogenesis. We induced SE in adult male mice by intrahippocampal kainic acid (KA) infusion. Acute administration of a cocktail of adrenergic receptor antagonists (propranolol, prazosin, and atipamezole: PPA), enhanced glymphatic flow and effectively reduced the severity of spontaneous seizures in the chronic phase. The PPA treatment also reduced reactive gliosis and inhibited the loss of polarized expression of AQP4 water channels in the vascular endfeet of astrocytes. Administration of PPA after cessation of SE (30 hours post KA) also effectively suppressed epileptogenesis and improved outcome. Conversely, mice with constitutively low glymphatic transport due to genetic deletion of the aquaporin 4 (AQP4) water channel showed exacerbation of KA-induced epileptogenesis. We conclude that the pharmacological modulation of glymphatic fluid transport may represent a potential strategy to dampen epileptogenesis and the occurrence of spontaneous seizures following KA-induced SE.

Suggested Citation

  • Qian Sun & Sisi Peng & Qiwu Xu & Pia Weikop & Rashad Hussain & Wei Song & Maiken Nedergaard & Fengfei Ding, 2024. "Enhancing glymphatic fluid transport by pan-adrenergic inhibition suppresses epileptogenesis in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53430-y
    DOI: 10.1038/s41467-024-53430-y
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    References listed on IDEAS

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    1. Lauren M. Hablitz & Virginia Plá & Michael Giannetto & Hanna S. Vinitsky & Frederik Filip Stæger & Tanner Metcalfe & Rebecca Nguyen & Abdellatif Benrais & Maiken Nedergaard, 2020. "Circadian control of brain glymphatic and lymphatic fluid flow," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Rashad Hussain & Jeffrey Tithof & Wei Wang & Arokoruba Cheetham-West & Wei Song & Weiguo Peng & Björn Sigurdsson & Daehyun Kim & Qian Sun & Sisi Peng & Virginia Plá & Douglas H. Kelley & Hajime Hirase, 2023. "Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema," Nature, Nature, vol. 623(7989), pages 992-1000, November.
    3. Li-Feng Jiang-Xie & Antoine Drieu & Kesshni Bhasiin & Daniel Quintero & Igor Smirnov & Jonathan Kipnis, 2024. "Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance," Nature, Nature, vol. 627(8002), pages 157-164, March.
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