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Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the [sup.125]I galanin--binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target. galanin | seizure | G protein-coupled receptor | status epilepticus doi/ 10.1073/pnas.1008986107

The past decades have brought several advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs (AEDs), more than one-third of patients are resistant to pharmacological treatment. Furthermore, current AEDs do not prevent the development and progression of epilepsy. Thus, there is an urgent need to develop new therapies for AED-resistant patients, for prevention of epilepsy in patients at risk and for disease modification. Cell replacement and gene therapies have been proposed to offer potential approaches for improvements in therapy, but are such approaches really more promising than new pharmacological strategies? Here we critically review and discuss data from epilepsy models and human tissue studies indicating that cell and gene therapies might provide alternative therapeutic approaches for AED-resistant focal epilepsies and might have antiepileptogenic or disease-modifying potential. However, several crucial issues remain to be resolved to develop cell and gene therapies into effective and safe therapies.

Clinical data demonstrate that certain antiepileptic drugs including carbamazepine (CBZ) decrease serum biotin concentration 45-50% and increase urine and serum organic acids, which is suggestive of reduced function of biotin-dependent enzymes. However, little is known about biotin-dependent enzyme function at the tissue level in patients undergoing long-term CBZ treatment. We recently established that dietary CBZ administration to rats increases brain lactate and also decreases specific enzymatic activity and the relative abundance of hepatic biotinylated pyruvate carboxylase (PC). To examine the mechanism of altered activity and abundance of biotinylated PC, the effect of orally administered CBZ on hepatic PC protein and mRNA expression was examined in rats consuming a physiologically relevant level of dietary biotin (0.06 mg/kg). Rats were fed 0 or 3.4 g CBZ/kg diet for 28 d, a dose designed to achieve clinically relevant serum CBZ concentrations. Hepatic biotinylated PC and PC activity were significantly reduced by ~43 and 30%, respectively, in the drug-treated group. Liver PC protein expression and mRNA were ~43 and 35% lower, respectively, in the drug-treated group than in controls. Brain biotinylated PC was significantly lower (29%), whereas specific enzymatic activity was 175% higher in rats consuming the 3.4 g CBZ/kg diet. Brain, but not serum, lactate was significantly higher in rats consuming CBZ. Taken together, the lower PC protein and mRNA expression provide a plausible biochemical mechanism to explain the decreased abundance of biotinylated hepatic PC observed in previous studies. KEY WORDS: * carbamazepine * biotin * rats * antiepileptic drug * pyruvate carboxylase

Anxiety is a fundamental aspect of the human experience. It can be an adaptive response to a perceived threat, with both psychological and physiological features. In the short term, anxiety [...]

Psychiatrists are often asked to medicate patients with chronic kidney disease (CKD). Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with [...]