Elsevier

Epilepsy Research

Volume 85, Issues 2–3, August 2009, Pages 142-149
Epilepsy Research

Review
Blood–brain barrier breakdown-inducing astrocytic transformation: Novel targets for the prevention of epilepsy

https://doi.org/10.1016/j.eplepsyres.2009.03.005Get rights and content

Summary

Epileptogenesis is common following brain insults such as trauma, ischemia and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Recent studies demonstrated impaired integrity of the blood–brain barrier (BBB) during epileptogenesis. Here we review accumulating experimental evidence supporting the potential involvement of primary BBB lesion in epileptogenesis. Data from animal experiments demonstrate that primary breakdown of the BBB prone animals to develop focal neocortical epilepsy that is followed by neuronal loss and impaired functions. The extravasation of albumin from the circulation into the brain neuropil was found to be sufficient for the induction of epileptogenesis. Albumin binds to transforming growth factor β receptor 2 (TGFβR2) in astrocytes and induces rapid transcriptional modifications, astrocytic transformation and dysfunction. We highlight a novel cascade of events which is initiated by increased BBB permeability, eventually leading to neuronal dysfunction, epilepsy and cell loss. We review potential mechanisms and existing experimental evidence for the important role of astrocytes and the TGFβ pathway in epileptogenesis. Finally, we review evidence from human clinical data supporting the involvement of BBB lesion in epilepsy. We propose that primary vascular injury, and specifically BBB breakdown and repair, are key elements in altered interactions within the neurovascular unit and thus may serve as new therapeutic targets.

Section snippets

Injury-related epileptogenesis: a potential role for blood–brain barrier disruption and serum-derived albumin

Focal epilepsy typically arises from neuronal tissue either within or adjacent to a cortical lesion (Willoughby, 2000). The focus of epileptic tissue is often located in the hippocampal formation within the temporal lobe (temporal lobe epilepsy, TLE). Neurosurgical removal of the epileptogenic area in many patients leads to control or even abolishment of seizures. However, in light of the high rate of drug resistant focal epilepsies, and other neurological impairments following insults to the

The role of glia cells in epileptogenesis

The interactions observed between serum albumin and astrocytes, followed by astrocytic transformation and dysfunction early during epileptogenesis suggest a key role for astrocytes in the epileptogenic process. Indeed, proliferation of astrocytes is a pathological hallmark in many patients with TLE. Recent studies have implicated novel physiological roles for glia cells in the CNS, such as modulation of synaptic transmission and plasticity. Accumulating evidence show clear changes in the

The TGFβ pathway and epileptogenesis

TGFβs are pleiotropic cytokines that play a pivotal role in intercellular communication (for review see Massague, 2000, Shi and Massague, 2003), and their signaling pathways are frequently involved in cell growth, embryogenesis, differentiation, morphogenesis, wound healing, immune response, and apoptosis in a wide variety of cells (Blobe et al., 2000, Flanders et al., 1991, Gold and Parekh, 1999). TGFβ signaling is mediated mainly by two serine threonine kinase receptors, TGFβRI and TGFβRII,

Detection of BBB damage in the human epileptic brain

Is there any evidence in human studies for the involvement of pathology at the BBB and epileptogenesis? As mentioned above, pathological and immunohistochemical studies in human epileptic tissue consistently demonstrated structural evidence for abnormal BBB and serum albumin within the neuropil and cellular elements as functional evidence for abnormal vessels permeability for large hydrophilic molecules. These data call for the development of strategies to detect BBB permeability changes for

Acknowledgments

Supported by the Sonderforschungsbereich TR3 (AF and UH), the Israeli Science Foundation (566/07, AF), the Binational US–Israel Foundation (BSF 2007185, AF and DK) and the CURE foundation (DK and AF). The authors thank Dr. Dominik Zumsteg for helping with the illustration.

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