Polysialylation is a post‐translational modification of the neural cell adhesion molecule (NCAM), which in the adult brain promotes structural changes in regions of neurogenesis and neuroplasticity. Because a variety of plastic changes including neurogenesis have been suggested to be functionally involved in the pathophysiology of epilepsies, it is of specific interest to define the impact of the polysialic acid (PSA)‐NCAM system on development of this disease and associated comorbidities. Therefore, we studied the impact of transient enzymatic depolysialylation of NCAM on the pathophysiology in an electrically induced rat post‐status epilepticus (SE) model. Loss of PSA counteracted the SE‐induced increase in neurogenesis in a significant manner. This effect of endoneuraminidase (endoN) treatment on hippocampal neurogenesis did not impact the subsequent development of spontaneous seizures. In contrast, transient lack of PSA during SE and in the early phase of epileptogenesis exhibited a cognition sparing effect as revealed in the Morris water maze paradigm. In conclusion, our data do not support a central role of neurogenesis in the development of a hyperexcitable epileptic network. However, in view of the cognition‐sparing effect, the transient modulation of the PSA‐NCAM system seems to allow beneficial long‐term disease modification, which might be mediated by the partial normalization of neurogenesis.

Background and purpose:A functional link between seizure-induced P-glycoprotein overexpression at the blood-brain barrier and therapeutic failure has been suggested by several studies using rodent epilepsy models and human epileptic tissue. Recently, we reported that interference with the mechanisms that up-regulate P-glycoprotein in response to seizure activity might provide a novel approach to control its expression in the epileptic brain. Based on these data, we hypothesized that blocking the appropriate signalling cascade by cyclooxygenase-2 inhibition should improve brain penetration of antiepileptic drugs and help to overcome drug resistance. Experimental approach: Effects of the selective cyclooxygenase-2 inhibitor celecoxib on the response to the P-glycoprotein substrate, phenobarbital, was evaluated in a chronic model of drug-resistant temporal lobe epilepsy in rats. Drug-resistant rats selected from this model exhibit a marked overexpression of P-glycoprotein in the hippocampus and other limbic brain regions. Key results: Responders and non-responders were selected from a group of rats with spontaneous recurrent seizures after prolonged treatment with phenobarbital at maximum tolerated doses. The efficacy of phenobarbital was re-evaluated following a 6 day treatment with celecoxib and the frequency of spontaneous recurrent seizures was significantly reduced in both groups of rats, phenobarbital responders or non-responders selected from the previous drug trial. Conclusions and implications:Pretreatment with the cyclooxygenase-2 inhibitor restored the anticonvulsant activity of phenobarbital in rats that failed to exhibit a relevant response before celecoxib treatment. Our data provide further support for a novel therapeutic approach to overcome transporter-mediated drug resistance in epilepsies.

SUMMARYPurpose: Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. Methods: We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [18 F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders.

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BackgroundThe Y-box binding protein 1 (YB-1) is considered to be one of the key regulators of transcription and translation. However, so far only limited knowledge exists regarding its cellular distribution in the adult brain.ResultsAnalysis of YB-1 immunolabelling as well as double-labelling with the neuronal marker NeuN in rat brain tissue revealed a predominant neuronal expression in the dentate gyrus, the cornu ammonis pyramidal cell layer, layer III of the piriform cortex as well as throughout all layers of the parahippocampal cortex. In the hilus of the hippocampus single neurons expressed YB-1. The neuronal expression pattern was comparable in the hippocampus and parahippocampal cortex of adult macaques and humans. Double-labelling of YB-1 with the endothelial cell marker Glut-1, the multidrug transporter P-glycoprotein, and the astrocytic marker GFAP did not indicate a co-localization. Following status epilepticus in rats, no induction of YB-1 occurred in brain capillary endothelial cells and neurons.ConclusionIn conclusion, our study demonstrates that YB-1 is predominantly expressed in neurons in the adult brain of rats, macaques and humans. Lack of a co-localization with Glut-1 and P-glycoprotein argues against a direct role of YB-1 in the regulation of blood-brain barrier P-glycoprotein.