Seizure suppression by GDNF gene therapy in animal models of epilepsy.
Temporal lobe epilepsy patients remain refractory to available anti-epileptic drugs in 30% of cases, indicating a need for novel therapeutic strategies. In this context, glial cell line-derived neurotrophic factor (GDNF) emerges as a possible new agent for epilepsy treatment. However, a limited number of studies, use of different epilepsy models, and different methods of GDNF delivery preclude understanding of the mechanisms for the seizure-suppressant action of GDNF. Here we show that recombinant adeno-associated viral (rAAV) vector-based GDNF overexpression in the rat hippocampus suppresses seizures in two models of temporal lobe epilepsy. First, when rAAV-GDNF was injected before hippocampal kindling, the number of generalized seizures decreased, and the prolongation of behavioral convulsions in fully kindled animals was prevented. Second, injection of rAAV-GDNF after kindling increased the seizure induction threshold. Third, rAAV-GDNF decreased the frequency of generalized seizures during the self-sustained phase of status epilepticus. Our data demonstrate the complexity of mechanisms and the beneficial action of GDNF in epilepsy. Furthermore, we show that ectopic rAAV-mediated GDNF gene expression in the seizure focus is a feasible way to mitigate seizures and provides proof of principle that the neurotrophic factor-based gene therapy approach has the potential to be developed as alternative strategy for epilepsy treatment.
Kanter-Schlifke
Irene
I
Experimental Epilepsy Group, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden.
Georgievska
Biljana
B
Kirik
Deniz
D
Kokaia
Merab
M
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004827:Epilepsy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D004833:Epilepsy, Temporal Lobe / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007696:Kindling, Neurologic; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D051100:Glial Cell Line-Derived Neurotrophic Factor