Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGF Delta b1 regulation

Keywords: astrocytes; epilepsy; microglia; neuroinflammation; connexin 43; pH; cytokines; levetiracetam BACKGROUND AND PURPOSE The involvement of astrocytes as immune-competent players in inflammation and the pathogenesis of epilepsy and seizure-induced brain damage has recently been recognized. In clinical trials and practice, levetiracetam (LEV) has proven to be an effective antiepileptic drug (AED) in various forms of epileptic seizures, when applied as mono- or added therapy. Little is known about the mechanism(s) of action of LEV. Evidence so far suggests a mode of action different from that of classical AEDs. We have shown that LEV restored functional gap junction coupling and basic membrane properties in an astrocytic inflammatory model in vitro. EXPERIMENTAL APPROACH Here, we used neonatal rat astrocytes co-cultured with high proportions (30%) of activated microglia or treated with the pro-inflammatory cytokine interleukin-1 Delta *b to provoke inflammatory responses. Effects of LEV (50 mu g.mL-1) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGF Delta *b1 (by elisa) were studied in these co-cultures. KEY RESULTS LEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGF Delta *b1 expression in inflammatory and control co-cultures. Furthermore, LEV and TGF Delta *b1 exhibited similar facilitating effects on the generation of astrocyte voltage-gated currents in inflammatory co-cultures and the effects of LEV were prevented by antibody to TGF Delta *b1. CONCLUSIONS AND IMPLICATIONS Our data suggest that LEV is likely to reduce the harmful spread of excitation elicited by seizure events within the astro-glial functional syncytium, with stabilizing consequences for neuronal-glial interactions.