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

Nikitidou, Litsa LU (2013) In Lund University Faculty of Medicine Doctoral Dissertation Series 2013:33.
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... (More)
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. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Epilepsi är en allvarlig kronisk neurologisk sjukdom, som drabbar ungefär 1% av befolkningen. Sjukdomen yttrar sig genom plötsliga återkommande krampanfall, som beror på en obalans i hjärnan mellan hämmande (inhibitoriska) och stimulerande (excitatoriska) nervimpulser. När de stimulerande impulserna tar överhand leder detta till överstimulering, också kallad för hyperexcitabilitet, som ger upphov till epileptiska kramper. Symptomen behandlas med väletablerade

antiepileptiska läkemedel men mer än var tredje patient svarar inte som förväntat på behandlingen utan den epileptiska aktiviteten blir återkommande. För att öka livskvalitén hos epilepsipatienter genom att förebygga epileptiska... (More)
Popular Abstract in Swedish

Epilepsi är en allvarlig kronisk neurologisk sjukdom, som drabbar ungefär 1% av befolkningen. Sjukdomen yttrar sig genom plötsliga återkommande krampanfall, som beror på en obalans i hjärnan mellan hämmande (inhibitoriska) och stimulerande (excitatoriska) nervimpulser. När de stimulerande impulserna tar överhand leder detta till överstimulering, också kallad för hyperexcitabilitet, som ger upphov till epileptiska kramper. Symptomen behandlas med väletablerade

antiepileptiska läkemedel men mer än var tredje patient svarar inte som förväntat på behandlingen utan den epileptiska aktiviteten blir återkommande. För att öka livskvalitén hos epilepsipatienter genom att förebygga epileptiska kramper, samt att kunna ersätta en mångårig medicinsk behandling med svåra biverkningar krävs nya och mer effektiva behandlingsalternativ.

I hjärnan finns naturligt förekommande proteiner, ett exempel är neurotrofiska faktorer, som påverkar överlevnad och tillväxt av hjärnceller. Det finns också neuropeptider, som påverkar signalering mellan hjärnceller. Både neurotrofiska faktorer och neuropeptider har visat sig ha en hämmande roll vid epileptisk aktivitet i hjärnan. I den här avhandlingen har vi fokuserat på två neuropeptider och en neurotrofiska faktor som har uppvisat anti-epileptiska egenskaper,

nämligen vaskulär endotelcellstillväxtfaktor (VEGF), neuropeptid Y (NPY) och galanin. För att studera dessa proteiner närmare, har vi använt oss av djurmodeller för epilepsi. Genom att förstärka uttrycket av dessa naturligt förekommande ämnen samt deras receptorer i hjärnan på försöksdjur har vi undersökt effekten på epileptiska kramper. Nivåerna har förstärkts genom tre olika strategier. I den

första studien användes transgena möss, där en genetisk förändring påverkar uttrycket av VEGF receptor 2 (Flk-1). I den andra studien utvecklades genetiskt modifierade celler för att frisätta galanin som sedan placerades i speciella membran och implanterades i hjärnan i området där den epileptiska aktiviteten uppkommer. Cellerna kan på så sätt frisätta galanin genom det semipermeabla membranet samtidigt som de inkapslade cellerna kan ta upp näringsämnen från den omkringliggande vävnaden för överlevnad. De inkapslade cellerna integreras inte med den kroppsegna vävnaden, vilket möjliggör att de inkapslade cellerna kan avlägsnas vid eventuella biverkningar. I den tredje och fjärde studien undersöktes den hämmande effekten av epileptiska kramper genom att förstärka uttrycket av både NPY och antingen Y2 eller Y5 receptorer. När NPY uttrycks i kombination

med en av sina receptorer ökar effekten av behandlingen.

Genom att förstärka uttrycket av ovannämnda proteiner samt deras receptorer i hjärnan har vi kunnat reducera antalet, varaktigheten och svårighetsgraden av epileptiska kramper. Med ökat uttryck av VEGF receptor 2 (Flk-1) och med galanin har mildare epileptiska kramper kunnat hämmas. Den kombinatoriska behandlingen, med NPY och antingen Y2 eller Y5 receptorer påverkade även svårare generaliserade kramper, vilket gör den lämplig som en alternativ behandling för epilepsi. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor de Curtis, Marco, Istituto Neurologico Carlo Besta, Milan, Italy
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Epilepsy, Gene Therapy, Neuropeptide Y, Y2 receptor, Y5 receptor, Galanin, Encapsulated cell biodelivery, Vascular endothelial growth factor, Flk-1, Hippocampus
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2013:33
pages
110 pages
publisher
Neurology, Lund
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2013-03-22 09:15:00
ISSN
1652-8220
ISBN
978-91-87449-03-1
language
English
LU publication?
yes
id
3d90afd5-29c3-49f1-a092-41e3aa82dfb3 (old id 3559258)
date added to LUP
2016-04-01 13:21:47
date last changed
2019-05-22 00:32:37
@phdthesis{3d90afd5-29c3-49f1-a092-41e3aa82dfb3,
  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.},
  author       = {Nikitidou, Litsa},
  isbn         = {978-91-87449-03-1},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {Neurology, Lund},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Neuropeptides and neurotrophic factors in epilepsy: seizure suppressant actions of VEGF, NPY and galanin},
  url          = {https://lup.lub.lu.se/search/ws/files/3325974/3559266.pdf},
  volume       = {2013:33},
  year         = {2013},
}