Publikation
Anti-Inflammatory Effects of the Anticonvulsant Drug Levetiracetam on Electrophysiological Properties of Astroglia Are Mediated Via TGF-ß1 Regulation
Konferenzpapier/Poster - 09.04.2011
Stienen Martin N., Prochnow Nora, Haghikia Aiden, Hinkerohe Daniel, Faustmann Pedro M., Dermietzel Rolf
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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.