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Astrocytes are increasingly associated to act as putative targets of affection in the pathogenesis of epilepsy and seizure induced tissue damage in the central nervous system. 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.

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 peripheral microglia was stimulated with the proinflammatory cytokine interleukin1-beta (IL1-b) for 2 hours prior to whole cell patch clamp recordings in the voltage clamp mode in vitro. Co-cultures with low portions of microglia (M5%) served as controls and were basis for IL1-b induction of an inflammatory state. Immunocytochemistry against ED1 was used for quantification of the microglial portions and evaluation of the state of activation.

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 were able to show 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 fact whether inflammation was induced by high levels of activated microglia or previous application of IL1-b and remained absent in controls. Furthermore, expression of the anti-inflammatory cytokine transforming growth factor- beta1 (TGF-b1) could be proven to be upregulated in the presence of LEV.

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- b1 operated way. Thus, LEV might serve as a tool to restore depolarized astrocytic membrane resting potentials during inflammation and provides a way to reduce excitation mediated Ca2+-wave spread and toxicity in glial tissues.