Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation.
OBJECTIVE
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.


METHODS
Here, we used neonatal rat astrocytes co-cultured with high proportions (30%) of activated microglia or treated with the pro-inflammatory cytokine interleukin-1β to provoke inflammatory responses. Effects of LEV (50 µg·mL⁻¹) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGFβ1 (by (ELISA)) were studied in these co-cultures.


RESULTS
LEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGFβ1 expression in inflammatory and control co-cultures. Furthermore, LEV and TGFβ1 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 TGFβ1.


CONCLUSIONS
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.
Institute of Neuroanatomy, Ruhr-University, Bochum, Germany. martin.stienen@rub.de
Martin N
MN
Stienen
Aiden
A
Haghikia
Hannes
H
Dambach
Jan
J
Thöne
Martin
M
Wiemann
Ralf
R
Gold
Andrew
A
Chan
Rolf
R
Dermietzel
Pedro M
PM
Faustmann
Daniel
D
Hinkerohe
Nora
N
Prochnow
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D018920:Coculture Techniques; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D000077287:Levetiracetam; D008564:Membrane Potentials / Q000187:drug effects; D017628:Microglia / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D053583:Interleukin-1beta; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000077287:Levetiracetam; D010889:Piracetam