Neuropeptides and neurotrophic factors in epilepsy: seizure suppressant actions of VEGF, NPY and galanin

Abstract: Epilepsy is a severe chronic neurological disorder, affecting about 1% of the population. The disease is manifested by spontaneous recurrent seizures, caused by hypersynchronized neuronal activity due to imbalance in the brain between the inhibition and excitation. Symptoms are treated with anti-epileptic drugs, but unfortunately, 30-40% of patients respond poorly to current treatment. Therefore, more efficient treatments with disease modifying or curing effects need to be developed. In the brain there are naturally occurring endogenous proteins affecting the survival and growth of brain cells, called neurotrophic factors. There are also neuropeptides, which are involved in signaling between brain cells. Both neurotrophic factors and neuropeptides have been shown to have an important role in suppressing epileptic activity. In this thesis, we focused on one neurotrophic factor and two neuropeptides that have demonstrated anti-epileptic properties; vascular endothelial growth factor (VEGF), neuropeptide Y (NPY), and galanin. To study these molecules, we have used different animal models of epilepsy and investigated the effect on epileptic seizures by enhancing the expression of these endogenously occurring proteins and/or their receptors in the brain of experimental animals. The levels of NPY, NPY receptors (Y2 or Y5), galanin and VEGF receptor 2 (Flk-1) were enhanced by using three different strategies. In the first study, we used genetically modified transgenic mice that increase the expression of VEGF receptor 2. In the second study, genetically modified cells were developed to release galanin. These cells were then placed into special capsules built of semipermeable membranes and subsequently implanted in the brain. The cells could thereby release galanin into the tissue through the membrane and in turn receive nutrients from the surrounding tissue. This approach has the advantage that, in case of adverse effects, the capsules filled with genetically modified cells easily can be removed from the brain. In the third and fourth studies we examined the effects of the combinatorial gene therapy of NPY and either Y2 or Y5 receptors on epileptic seizures by enhancing their expression with viral vectors. By enhancing the expression of the mentioned proteins and receptors in the brain, we have been able to reduce the number, duration and severity of epileptic seizures in animal models. Increased expression of VEGF receptor 2 (Flk-1) or increased extracellular levels of galanin by encapsulated cell biodelivery (ECB) inhibited focal epileptic seizures. The combinatorial treatmentwith NPY and either Y2 or Y5 receptors, on the other hand, also affected generalized seizures. All these approaches, particularly the viral vector-based treatment, have a potential to be developed into an alternative treatment strategies for epilepsy.