Anti-Inflammatory Effects of the Anticonvulsant Drug Levetiracetam on Electrophysiological Properties of Astroglia Are Mediated Via TGF-ß1 Regulation

Publication

Anti-Inflammatory Effects of the Anticonvulsant Drug Levetiracetam on Electrophysiological Properties of Astroglia Are Mediated Via TGF-ß1 Regulation

Conference Paper/Poster - Apr 9, 2011

Stienen Martin N., Prochnow Nora, Haghikia Aiden, Hinkerohe Daniel, Faustmann Pedro M., Dermietzel Rolf

Units

Neurochirurgie

Keywords

Levetiracetam, Epilepsy, Glia, Inflammation, Cytokines

Contact

Martin N. Stienen

Citation

Stienen M, Prochnow N, Haghikia A, Hinkerohe D, Faustmann P, Dermietzel R (2011). Anti-Inflammatory Effects of the Anticonvulsant Drug Levetiracetam on Electrophysiological Properties of Astroglia Are Mediated Via TGF-ß1 Regulation.

Type

Conference Paper/Poster (Deutsch)

Conference Name

63rd Annual Meeting of the American Academy of Neurology (Honolulu, Hawaii, USA)

Publication Date

Apr 9, 2011

Publisher

N/A

Brief description/objective

OBJECTIVE: In the present study we investigated the influence of the anti-epileptic drug levetiracetam (LEV; Keppra) on the evoked voltage gated current responses of astrocytes under acute inflammatory conditions in an astroglial syncytium in vitro.

BACKGROUND: Astrocytes are increasingly appreciated as putative targets in the pathogenesis of epilepsy and seizure induced tissue damage in the central nervous system.

DESIGN/METHODS: For this purpose primary glial cell cultures were prepared from brain hemispheres of postnatal Wistar rats. To reach an (pro-)inflammatory state in culture, astrocytes were either co-cultured with high amounts of microglia (M30%) or cultures containing low portions of microglia (M5%) were stimulated with the proinflammatory cytokine interleukin1-beta (IL1-ß) for 2 hours prior to whole cell patch clamp recordings in vitro. M5% co-cultures furthermore served as controls.

RESULTS: Electrophysiology revealed that LEV application during the inflammatory state shifted depolarized astrocytic membrane resting potentials back towards control values of non-inflammatory conditions. Mimicking inflammatory conditions, we observed a highly significant increase in the astrocytic inward rectifier
mediated current response due to strong hyperpolarization (<-80 mV) and an increased outward rectification at holding potentials >-30 mV. This effect could be observed independently from the inflammatory setting used and remained absent in controls. Furthermore, expression of the anti-inflammatory cytokine transforming growth factor-beta1 (TGF-ß1) could be proven to be upregulated in the presence of LEV and effects of TGF-ß1 on glial membrane currents could be blocked by antibody neutralization.

CONCLUSIONS: In summary, we suggest that the effect of LEV is mediated in two ways: first, via Kir-channel activation and second via an unspecific impact on outward rectifier in a TGF-ß1 operated way. Thus, LEV might serve as a tool to restore depolarized astrocytic membrane resting potentials during inflammation and provide a way to reduce excitation mediated Ca2+-wave spread and toxicity in brain tissue.