Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex

Abstract

Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown.In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4 -7 d after treatment and could be recorded up to 49 d postoperatively in Ͼ60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised bloodbrain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

“…In rat, transient opening of the BBB is sufficient for induction of focal epileptogenesis (Seiffert et al, 2004). BBB lesion is also considered a primary event in human TLE, leading to the extravasation of serum albumin which is taken up by neurons, astrocytes, and microglia (Seiffert et al, 2004;Van Vliet et al, 2007). In contrast, no changes in astrocyte Kir currents were observed in a systemic kainate rat model, 7-16 days following status epilepticus (SE) (Takahashi et al, 2010).…”

The Blood-Brain Barrier and Epilepsy

“…Experimental evidence also supports a role of intravascular inflammation, often associated with BBB damage, in seizure disorders (Marchi et al, 2007a;Marchi et al, 2009;Seiffert et al, 2004;van Vliet et al, 2007). Recently, the association between circulating immune cells, their interaction with the BBB, and seizure propensity was proposed; leukocyte adhesion was shown to directly support ictogenesis in the pilocarpine model of seizures (Fabene et al, 2008).…”

“…While large amount of published data support a correlation between occurrence of spontaneous epileptic seizures, seizures and abnormal BBB, direct evidence for the involvement of BBB breakdown in epileptogenesis has been only recently confirmed by the studies, in which opening of the BBB was sufficient to induce delayed epileptiform activity Seiffert et al, 2004).…”

The Role of Astrocytes in Epileptogenesis

“…Recently, it was elegantly demonstrated in rats that albumin can act directly on astrocytes, thereby facilitating epileptogenesis 2004, Ivens et al;Van Vliet et al;. It has been shown that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes that is mediated by TGF-R.…”