Biomedical subjects

Ernst Seiffert

Publications and source records attributed to Ernst Seiffert.

3 recordsLinked to original sources

PubMed2006

TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis.

It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5-49 days after treatment, but only 14% (n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor beta receptors (TGF-betaRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-d-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-betaR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% (n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-betaRs as a possible therapeutic target.

Animals↗

PubMed2005

Persistent BBB disruption may underlie alpha interferon-induced seizures.

Generalized seizures during Interferon-alpha (IFN-alpha) therapy have been repeatedly described in about 1%-4% of patients. However, the mechanisms underlying IFN-alpha induced seizures are not known. We describe a patient who developed partial and secondary generalized seizures during IFN-alpha therapy while displaying a focal disruption of her blood-brain barrier (BBB) corresponding with pathological electroencephalography (EEG). To test our hypothesis that IFN-alpha induces seizure activity, we exposed rat somatosensory cortices to clinically relevant concentrations of IFN-alpha in the acute in-vitro slice preparation or in-vivo. While acute exposure did not induce epileptic activity, recordings from slices exposed to IFN-alpha in-vivo one week prior to recordings revealed pronounced epileptiform activity in > 80% of the slices. We propose that cortical exposure to IFN-alpha leads to the generation of an epileptic cortex, which explains the weeks of latency in patients from initial treatment to seizures, and stressing the importance of identifying possible BBB disruption among high-risk patients administered peripherally acting drugs.

Action Potentials↗

PubMed2004

Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex.

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 >60% 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 blood-brain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.

2-Amino-5-phosphonovalerate↗