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Extending the classical neurocentric view that epileptogenesis is driven by neuronal alterations, accumulating experimental and clinical evidence points to the possible involvement of non-neuronal cells, such as glia, endothelial cells, and leukocytes in the pathophysiology of epilepsy, specifically by means of inflammatory mechanisms.

Inflammatory responses, notably interleukin (IL)-1β signaling, have been shown to be associated with status epilepticus and seizure frequency (Marchi et al., 2009). As shown in experimental models and in tissue from patients with epilepsy, seizures evoke the release of cytokines not just from neurons but also from glial cells and endothelial cells (Ravizza et al., 2008). Furthermore, the contribution of non-neuronal cells to the induction of neuronal death following pilocarpine-induced status epilepticus has been demonstrated (Rogawsi, 2005; Ding et al., 2007).

Several key events that lead to inflammatory responses following seizures have been identified. Seizures can induce blood–brain barrier disruption (Janigro, 2007) and/or angiogenesis characterized by poor barrier function (Rigau et al., 2007), thereby permitting serum albumin entry into the brain (van Vliet et al., 2007), followed by astrocytic albumin uptake (Ivens et al., 2007); and activation of endothelial and leukocytes interactions (Fabene et al., 2008; Kleen & Holmes, 2008; Ransohoff, 2009).

However, despite this wealth of data, the mechanisms underlying enduring immune and inflammatory responses in temporal lobe epilepsy (TLE) remain largely elusive. As described in the current issue of EJN, Aronica et al. (2010) took an important step toward resolving this issue. They demonstrated the selective up-regulation of a proinflammatory signalling-associated microRNA (miRNA) in a rat model of TLE as well as in human TLE.

MicroRNAs are genomically encoded small non-coding RNAs that influence the translation and stability of mRNAs (Zhao & Srivastava, 2007). Aronica et al. (2010) focused on miR-146a, a microRNA that is induced by pro-inflammatory stimuli, modulating innate immunity through regulation of Toll-like receptor signaling and cytokine responses (Taganov et al., 2006). miR-146a is also known to play a functional role in T lymphocyte-mediated immune responses (Curtale et al., 2010).

In order to understand the regulation and function of miR-146a in epilepsy, Aronica et al. (2010) investigated the dynamics of miR-146a expression during epileptogenesis in a rat model of TLE. Furthermore, they studied the expression and cellular distribution of this microRNA in hippocampal tissue obtained from TLE patients with hippocampal sclerosis. The authors report an increase of miR-146a expression in the CA3 region of rats during latent and chronic phases of experimental epilepsy, as well as in the human tissue. It is important to note that miR-146a expression was evident not only in neurons, but most prominently in GFAP-positive reactive astrocytes, underscoring their key role for orchestrating inflammatory responses in epilepsy.

The results of this study suggest new avenues toward the identification of cellular mechanisms underlying epileptogenesis and persistent functional alterations in chronic epilepsy. Furthermore, these results indicate that miRNAs, linking astrocytes with inflammatory mechanisms, are potentially promising new cellular targets for the development of antiepileptic drugs.

References

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  2. References
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