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Photopharmacological activation of adenosine A1 receptor signaling suppresses seizures in a mouse model for temporal lobe epilepsy

Jeroen Spanoghe (UGent) , Evelien Wynendaele (UGent) , Marijke Vergaelen (UGent) , Maren De Colvenaer (UGent) , Tina Mariman, Kristl Vonck (UGent) , Evelien Carrette (UGent) , Wytse Wadman (UGent) , Erine Craey, Lars Emil Larsen (UGent) , et al.
(2025) JOURNAL OF CONTROLLED RELEASE. 381.
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Abstract
Up to 30 % of epilepsy patients suffer from drug-resistant epilepsy (DRE). The search for innovative therapies is therefore important to close the existing treatment gap in these patients. The adenosinergic system possesses potent anticonvulsive effects, mainly through the adenosine A1 receptor (A1R). However, clinical application of A1R agonists is hindered by severe systemic side effects. To achieve local modulation of A1Rs, we employed a photopharmacological approach using a caged version of the A1R agonist N6-cyclopentyladenosine, termed cCPA. We performed the first in vivo study with intracerebroventricularly (ICV) administered cCPA to investigate the potential to photo-uncage and release sufficient amounts of cCPA in the hippocampus by local illumination in order to suppress hippocampal excitability and seizures in mice. We validated the presence of cCPA in the hippocampus after ICV injection and explored its pharmacokinetic profile and in vivo stability. Using hippocampal evoked potential recordings, we showed a reduction in hippocampal neurotransmission after photoreleasing CPA, similar to that obtained with ICV injection of CPA. Furthermore, in the intrahippocampal kainic acid mouse model for DRE, photo-release of CPA in the epileptic hippocampus resulted in a strong suppression of seizures. Finally, we demonstrated that intrahippocampal photo-release of CPA resulted in less impairment of motor performance in the rotarod test compared to ICV administration of CPA. These results provide a proof of concept for photopharmacological A1R modulation as an effective precision treatment for DRE.
Keywords
Photopharmacology, Photo-uncaging, Adenosine, Adenosine A 1 receptor, Epilepsy, Drug-resistant epilepsy, Temporal lobe epilepsy, A(1) RECEPTOR ACTIVATION, ADENOSINE RECEPTORS, HIPPOCAMPAL SCLEROSIS, BRAIN, ANALOGS, DELIVERY, RELEASE, GAMMA, RATS, N-6-CYCLOPENTYLADENOSINE

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Citation

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MLA
Spanoghe, Jeroen, et al. “Photopharmacological Activation of Adenosine A1 Receptor Signaling Suppresses Seizures in a Mouse Model for Temporal Lobe Epilepsy.” JOURNAL OF CONTROLLED RELEASE, vol. 381, 2025, doi:10.1016/j.jconrel.2025.113626.
APA
Spanoghe, J., Wynendaele, E., Vergaelen, M., De Colvenaer, M., Mariman, T., Vonck, K., … Raedt, R. (2025). Photopharmacological activation of adenosine A1 receptor signaling suppresses seizures in a mouse model for temporal lobe epilepsy. JOURNAL OF CONTROLLED RELEASE, 381. https://doi.org/10.1016/j.jconrel.2025.113626
Chicago author-date
Spanoghe, Jeroen, Evelien Wynendaele, Marijke Vergaelen, Maren De Colvenaer, Tina Mariman, Kristl Vonck, Evelien Carrette, et al. 2025. “Photopharmacological Activation of Adenosine A1 Receptor Signaling Suppresses Seizures in a Mouse Model for Temporal Lobe Epilepsy.” JOURNAL OF CONTROLLED RELEASE 381. https://doi.org/10.1016/j.jconrel.2025.113626.
Chicago author-date (all authors)
Spanoghe, Jeroen, Evelien Wynendaele, Marijke Vergaelen, Maren De Colvenaer, Tina Mariman, Kristl Vonck, Evelien Carrette, Wytse Wadman, Erine Craey, Lars Emil Larsen, Mathieu Sprengers, Jeroen Missinne, Serge Van Calenbergh, Bart De Spiegeleer, Dimitri De Bundel, Ilse Smolders, Paul Boon, and Robrecht Raedt. 2025. “Photopharmacological Activation of Adenosine A1 Receptor Signaling Suppresses Seizures in a Mouse Model for Temporal Lobe Epilepsy.” JOURNAL OF CONTROLLED RELEASE 381. doi:10.1016/j.jconrel.2025.113626.
Vancouver
1.
Spanoghe J, Wynendaele E, Vergaelen M, De Colvenaer M, Mariman T, Vonck K, et al. Photopharmacological activation of adenosine A1 receptor signaling suppresses seizures in a mouse model for temporal lobe epilepsy. JOURNAL OF CONTROLLED RELEASE. 2025;381.
IEEE
[1]
J. Spanoghe et al., “Photopharmacological activation of adenosine A1 receptor signaling suppresses seizures in a mouse model for temporal lobe epilepsy,” JOURNAL OF CONTROLLED RELEASE, vol. 381, 2025.
@article{01JWB89ZVW59RCPVH9YP0P0H1W,
  abstract     = {{Up to 30 % of epilepsy patients suffer from drug-resistant epilepsy (DRE). The search for innovative therapies is therefore important to close the existing treatment gap in these patients. The adenosinergic system possesses potent anticonvulsive effects, mainly through the adenosine A1 receptor (A1R). However, clinical application of A1R agonists is hindered by severe systemic side effects. To achieve local modulation of A1Rs, we employed a photopharmacological approach using a caged version of the A1R agonist N6-cyclopentyladenosine, termed cCPA. We performed the first in vivo study with intracerebroventricularly (ICV) administered cCPA to investigate the potential to photo-uncage and release sufficient amounts of cCPA in the hippocampus by local illumination in order to suppress hippocampal excitability and seizures in mice. We validated the presence of cCPA in the hippocampus after ICV injection and explored its pharmacokinetic profile and in vivo stability. Using hippocampal evoked potential recordings, we showed a reduction in hippocampal neurotransmission after photoreleasing CPA, similar to that obtained with ICV injection of CPA. Furthermore, in the intrahippocampal kainic acid mouse model for DRE, photo-release of CPA in the epileptic hippocampus resulted in a strong suppression of seizures. Finally, we demonstrated that intrahippocampal photo-release of CPA resulted in less impairment of motor performance in the rotarod test compared to ICV administration of CPA. These results provide a proof of concept for photopharmacological A1R modulation as an effective precision treatment for DRE.}},
  articleno    = {{113626}},
  author       = {{Spanoghe, Jeroen and Wynendaele, Evelien and Vergaelen, Marijke and De Colvenaer, Maren and Mariman, Tina and Vonck, Kristl and Carrette, Evelien and Wadman, Wytse and Craey, Erine and Larsen, Lars Emil and Sprengers, Mathieu and Missinne, Jeroen and Van Calenbergh, Serge and De Spiegeleer, Bart and De Bundel, Dimitri and Smolders, Ilse and Boon, Paul and Raedt, Robrecht}},
  issn         = {{0168-3659}},
  journal      = {{JOURNAL OF CONTROLLED RELEASE}},
  keywords     = {{Photopharmacology,Photo-uncaging,Adenosine,Adenosine A 1 receptor,Epilepsy,Drug-resistant epilepsy,Temporal lobe epilepsy,A(1) RECEPTOR ACTIVATION,ADENOSINE RECEPTORS,HIPPOCAMPAL SCLEROSIS,BRAIN,ANALOGS,DELIVERY,RELEASE,GAMMA,RATS,N-6-CYCLOPENTYLADENOSINE}},
  language     = {{eng}},
  pages        = {{16}},
  title        = {{Photopharmacological activation of adenosine A1 receptor signaling suppresses seizures in a mouse model for temporal lobe epilepsy}},
  url          = {{http://doi.org/10.1016/j.jconrel.2025.113626}},
  volume       = {{381}},
  year         = {{2025}},
}
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