Leakage of the blood–brain barrier (BBB) is associated with various neurological disorders, including temporal lobe epilepsy (TLE). However, it is not known whether alterations of the BBB occur during epileptogenesis and whether this can affect progression of epilepsy. We used both human and rat epileptic brain tissue and determined BBB permeability using various tracers and albumin immunocytochemistry. In addition, we studied the possible consequences of BBB opening in the rat for the subsequent progression of TLE. Albumin extravasation in human was prominent after status epilepticus (SE) in astrocytes and neurons, and also in hippocampus of TLE patients. Similarly, albumin and tracers were found in microglia, astrocytes and neurons of the rat. The BBB was permeable in rat limbic brain regions shortly after SE, but also in the latent and chronic epileptic phase. BBB permeability was positively correlated to seizure frequency in chronic epileptic rats. Artificial opening of the BBB by mannitol in the chronic epileptic phase induced a persistent increase in the number of seizures in the majority of rats. These findings indicate that BBB leakage occurs during epileptogenesis and the chronic epileptic phase and suggest that this can contribute to the progression of epilepsy.

To get insight into the mechanisms that may lead to progression of temporal lobe epilepsy, we investigated gene expression during epileptogenesis in the rat. RNA was obtained from three different brain regions [CA3, entorhinal cortex (EC), and cerebellum (CB)] at three different time points after electrically induced status epilepticus (SE): acute phase [group D (1 d)], latent period [group W (1 week)], and chronic epileptic period [group M (3–4 months)]. A group that was stimulated but that had not experienced SE and later epilepsy was also included (group nS). Gene expression analysis was performed using the Affymetrix Gene Chip System (RAE230A). We used GENMAPP and Gene Ontology to identify global biological trends in gene expression data. The immune response was the most prominent process changed during all three phases of epileptogenesis. Synaptic transmission was a downregulated process during the acute and latent phases. GABA receptor subunits involved in tonic inhibition were persistently downregulated. These changes were observed mostly in both CA3 and EC but not in CB. Rats that were stimulated but that did not develop spontaneous seizures later on had also some changes in gene expression, but this was not reflected in a significant change of a biological process. These data suggest that the targeting of specific genes that are involved in these biological processes may be a promising strategy to slow down or prevent the progression of epilepsy. Especially genes related to the immune response, such as complement factors, interleukins, and genes related to prostaglandin synthesis and coagulation pathway may be interesting targets.

Increasing evidence supports the involvement of inflammatory and immune processes in temporal lobe epilepsy (TLE). MicroRNAs (miRNA) represent small regulatory RNA molecules that have been shown to act as negative regulators of gene expression controlling different biological processes, including immune‐system homeostasis and function. We investigated the expression and cellular distribution of miRNA‐146a (miR‐146a) in a rat model of TLE as well as in human TLE. miR‐146a analysis in rat hippocampus was performed by polymerase chain reaction and immunocytochemistry at 1 week and 3–4 months after induction of status epilepticus (SE). Prominent upregulation of miR‐146a activation was evident at 1 week after SE and persisted in the chronic phase. The miR‐146a expression was confirmed to be present in reactive astrocytes. In human TLE with hippocampal sclerosis, increased astroglial expression of miR‐146a was observed mainly in regions where neuronal cell loss and reactive gliosis occurred. The increased and persistent expression of miR‐146a in reactive astrocytes supports the possible involvement of miRNAs in the modulation of the astroglial inflammatory response occurring in TLE and provides a target for future studies aimed at developing strategies against pro‐epileptogenic inflammatory signalling.

Accumulating evidence indicates an important pathophysiological role of brain inflammation in epilepsy. In this review, we will provide an update of specific inflammatory pathways that have been proposed to be crucial in the underlying molecular mechanisms of epilepsy, including the interleukin‐1 receptor/toll‐like receptor signalling, cyclooxygenase‐2, tumour necrosis factor‐alpha, complement signalling and chemokines. Furthermore, by drawing on evidence from preclinical and clinical studies we will discuss the potential of these signalling pathways targets for novel therapeutic interventions that control drug‐resistant seizures or have disease‐modifying effects. Finally, we will assess the use of these inflammatory pathways as potential biomarkers for the development of epilepsy or to measure the effectiveness of therapeutic interventions.