Abstracts

The glial cell line derived neurotrophic factor (GDNF) has recently been indicated as an endogeneous anti-epileptic agent, as well as it, due to its trophic action, could rescue neurons from excocytotic cell death and promote hippocampal neurogenesis. In the present study, we aimed to evaluate the ability of viral vector-mediated hippocampal overexpression of GDNF to supress seizures and alter seizure-induced cell death and neurogenesis., A recombinant adeno-associated viral vector (rAAV) encoding for GDNF or GFP (control) was injected in multiple sites of the hippocampal formation of rats. A recording/stimulating electrode was placed in the ventral hippocampus, and animals were stimulated either for 1 s once daily, inducing kindling epileptogenesis, or for 1 h continously to induce self-sustained status epilepticus (SE). Kindled animals were re-stimulated (i.e. re-kindled) four weeks following termination of kindling to assess the sustainability of hyperexcitability. Behavioural seizure activity (graded according to the scale of Racine) and EEG were recorded throughout the experiments. All experiments were conducted according to international ethical guidelines for animal care and were approved by the local ethical comittee., Using the kindling model, we found that transfection with rAAV-GDNF decreased the number of generalized seizures, prevented an increase of the duration of behavioural convulsions seen in re-kindled control animals, and increased the threshold for induction of re-kindled seizures. In the SE-model of epilepsy, animals overexpressing GDNF developed fewer generalized stage 5 seizures and exhibited a significantly better survival rate following SE. We further found that in GDNF-overexpressing animals, a higher proportion of new-born (BrdU+) cells acquired a neuronal fate, as determined by staining for DCX and Neun, compared to control animals. The SE-induced damage in hippocampal CA1/CA3 and dentate gyrus, as assessed by fluorojade staining, was unchanged by rAAV-GDNF transfection., Taken together, these data suggest that rAAV-mediated gene transfer is a feasible method for long-term delivery of GDNF to the seizure focus, and that such GDNF overexpression is able to suppress seizures in different animal models of epilepsy., (Supported by Swedish Research Council (Vetenskapsradet), the Segerfalk Foundation, the Craaford Foundation and the Kock[apos]s Foundation.)