Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy

Abstract

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 beta receptor 2 (TGFbetaR2) 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 TGFbeta 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.

Figure 1

A schematic illustration of BBB breakdown-induced brain response: within hours following BBB breakdown albumin diffuses into the brain’s extracellular space, binds to astrocytic TGFβ receptors and induces transcriptional change resulting in the transformation of astrocytes. Potential candidate changes are listed and include down-regulation of Kir4.1 and Glutamate transporters, connexins and glutamine synthase with up-regulation of pro-inflammatory cytokines (see text for details). The change in astrocytic functions leads within days to weeks to activity-dependent increase in neuronal excitability, hypersynchronicity and pathological plasticity which may eventually lead (within weeks–months) to excitotoxicity and damage.