Abstract
BackgroundCumulating evidence from rodent models points to a pathophysiological role of inflammatory signaling in the epileptic brain with Toll-like receptor-4 signaling acting as one key factor. However, there is an apparent lack of information about expression alterations affecting this pathway in canine patients with epilepsy. Therefore, we have analyzed the expression pattern of Toll-like receptor 4 and its ligands in brain tissue of canine patients with structural or idiopathic epilepsy in comparison with tissue from laboratory dogs or from owner-kept dogs without neurological diseases.ResultsThe analysis revealed an overexpression of Toll-like receptor-4 in the CA3 region of dogs with structural epilepsy. Further analysis provided evidence for an upregulation of Toll-like receptor-4 ligands with high mobility group box-1 exhibiting increased expression levels in the CA1 region of dogs with idiopathic and structural epilepsy, and heat shock protein 70 exhibiting increased expression levels in the piriform lobe of dogs with idiopathic epilepsy. In further brain regions, receptor and ligand expression rates proved to be either in the control range or reduced below control levels.ConclusionsOur study reveals complex molecular alterations affecting the Toll-like receptor signaling cascade, which differ between epilepsy types and between brain regions. Taken together, the data indicate that multi-targeting approaches modulating Toll-like receptor-4 signaling might be of interest for management of canine epilepsy. Further studies are recommended to explore respective molecular alterations in more detail in dogs with different etiologies and to confirm the role of the pro-inflammatory signaling cascade as a putative target.
Highlights
Cumulating evidence from rodent models points to a pathophysiological role of inflammatory signaling in the epileptic brain with Toll-like receptor-4 signaling acting as one key factor
Considering the prominent role of TLR4-signaling, we have focused this first study on the analysis of the distribution and expression rates of the TLR4 ligands high mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70)
In a recent proteomic study in rats, we have reported an early induction of HMGB1 in the hippocampus and of HSP70 in the hippocampus and parahippocampal cortex as a consequence of an electrically-induced status epilepticus [20]
Summary
Cumulating evidence from rodent models points to a pathophysiological role of inflammatory signaling in the epileptic brain with Toll-like receptor-4 signaling acting as one key factor. Increased expression rates of various pro-inflammatory mediators have been demonstrated in brain tissue from rodent epilepsy models as well as human patients with epilepsy [1, 6,7,8,9,10]. Among these mediators Toll-like receptor (TLR) signaling has been attributed a crucial role [2, 11]. Earlier studies reported that TLR4 antagonists exert anticonvulsant effects in two different acute seizure
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