Publikationsdatenbank

Regenerative medicine for the treatment of pharmacoresistant epilepsy? (2023)

Art

Vortrag

Autoren

Pauletti, A. (WE 14)

Li, S. (WE 14)

Gurlo, P. (WE 14)

Bröer, S. (WE 14)

Kongress

15th International Congress of the European Association for Veterinary Pharmacology and Toxicology

Bruges, Belgium, 02. – 05.07.2023

Quelle

Journal of veterinary pharmacology and therapeutics

Bandzählung: 46

Heftzählung: S1

Seiten: 47 – 48

ISSN: 1365-2885

Sprache

Englisch

Verweise

URL (Volltext): https://onlinelibrary.wiley.com/doi/10.1111/jvp.13207

DOI: 10.1111/jvp.13207

Kontakt

Institut für Pharmakologie und Toxikologie

Koserstr. 20
14195 Berlin
+49 30 838 53221
pharmakologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Introduction:
Epilepsies are among the most common chronic neurological disorders, affecting humans and animals alike. About 30% of human as well as 70% of canine patients do not become seizure-free despite treatment. Novel treatment approaches are desperately needed. One strategy could be cell therapy, which aims to regenerate inhibitory neurons in order to restore the balance between inhibition and excitation. Several experimental studies have shown seizure reduction or even seizure freedom after transplantation of GABAergic interneuron precursors and the first clinical study on cell therapy in human patients is enrolling. Alternatively, the stimulation of endogenous tissue repair by targeting neural stem cells (NSCs) in the hippocampus could be a less invasive approach. We are characterizing the fate of hippocampal NSCs in a translational model of epilepsy development in order to evaluate their potential as a therapeutic target.

Methods:
We performed an in-depth characterization of the hippocampal pathology and the time course and fate of NSCs in a mouse model of virus-induced seizures (Theiler's Murine Encephalomyelitis Virus). At 3, 7, 14 and 90 days post infection (dpi) C57BL/6 mice were euthanized and their brains sectioned for immunohistochemical analyses of degenerative and regenerative processes.

Results:
Similar to other non-infection-based models of epilepsy, we did observe a significant loss of inhibitory interneurons after virus infection. At 3–14 dpi we found NSC proliferation within the dentate gyrus to be significantly increased in infected mice. The amount of proliferation was correlated to the temporal proximity of the last seizure. In order to determine the cell fate, we compared the number of new-born neurons, which did not differ significantly between seizing and non-seizing or even mock-infected mice. However, mice with seizures displayed aberrant migration of immature neurons. Moreover, seizure proximity was linked to the number of glia progenitors. Seizure severity did not have an impact on proliferation.

Conclusions:
We confirmed that inhibitory neurons are lost in our model, thus increasing inhibition by endogenous regeneration could be a feasible therapeutic option. The larger number of NSCs entering the cell cycle after seizures, as well as their changed migration behavior could contribute to abnormal bursting and hyperexcitability. Another pro-epileptogenic mechanism is differentiation into glia, which contribute to inflammation and disease progression. Further experiments will evaluate whether aberrant neurogenesis can be inhibited and instead regenerative neurogenesis can be promoted to prevent seizures in infection-induced epilepsy.