Inflamed About Epilepsy

Science Signaling  13 Apr 2010:
Vol. 3, Issue 117, pp. ec111
DOI: 10.1126/scisignal.3117ec111

Epileptic seizures are often controlled by drugs that either dampen the activity of excitatory N-methyl-d-aspartate (NMDA) receptors or enhance the activity of inhibitory γ-aminobutyric acid (GABA) receptors; however, some 30% of patients are refractory to such treatments, which makes the search for new therapies an important goal (see commentary by Kleen and Holmes). Noting that the proinflammatory cytokine interleukin-1β (IL-1β) can enhance seizures, Maroso et al. investigated the interplay between inflammation and epilepsy by studying a role for Toll-like receptor 4 (TLR4), which shares signaling components with IL-1β, in mice that were induced to have seizures by the intrahippocampal injection of chemoconvulsants, including kainic acid (KA). Immunohistochemical analysis revealed that TLR4 was detectable in the neurons and astrocytes of KA-treated mice, but not untreated mice, and this was accompanied by an increase in the amount of high-mobility group box-1 (HMGB1), a chromatin-associated protein that is released from dying cells and that activates TLR4. HMGB1 was mainly produced by microglia. The authors saw a similar pattern of expression of TLR4 and HMGB1 proteins in hippocampal tissue from patients with temporal lobe epilepsy. Antagonists of HMGB1 and TLR4 inhibited the KA-dependent induction of seizures in mice, and C3H/HeJ mice, which have a nonfunctional TLR4, were resistant to KA-induced seizures. Ifenprodil, a blocker of certain NMDA receptor subunits, prevented the HMGB1-dependent enhancement in KA-induced seizures, suggesting that HMGB1 may increase excitotoxicity. Together, these data suggest that the HMGB1-TLR4 pathway may underlie the onset of seizures and thus provide a new therapeutic strategy to target epilepsy.

M. Maroso, S. Balosso, T. Ravizza, J. Liu, E. Aronica, A. M. Iyer, C. Rossetti, M. Molteni, M. Casalgrandi, A. A. Manfredi, M. E. Bianchi, A. Vezzani, Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 16, 413–419 (2010). [PubMed]

J. K. Kleen, G. L. Holmes, Taming TLR4 may ease seizures. Nat. Med. 16, 369–370 (2010). [PubMed]