Seizure suppression by GDNF gene therapy in animal models of epilepsy

被引:82
作者
Kanter-Schlifke, Irene
Georgievska, Biljana
Kirik, Deniz
Kokaia, Merab
机构
[1] Univ Lund Hosp, Wallenberg Neurosci Ctr, Expt Epilepsy Grp, S-22184 Lund, Sweden
[2] Lund Univ, Wallenberg Neurosci Ctr, Dept Expt Med Sci, Div Neurobiol, Lund, Sweden
[3] Lund Univ, Wallenberg Neurosci Ctr, Dept Expt Med Sci, CNS Dis Modeling Unit, Lund, Sweden
关键词
MIDBRAIN DOPAMINERGIC-NEURONS; KAINATE-INDUCED EXCITATION; NEUROTROPHIC FACTOR; RAT HIPPOCAMPUS; MESSENGER-RNAS; IN-VIVO; ELECTRICAL STIMULATION; ADENOASSOCIATED VIRUS; LIMBIC SEIZURES; DENTATE GYRUS;
D O I
10.1038/sj.mt.6300148
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
引用
收藏
页码:1106 / 1113
页数:8
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