Localized delivery of fibroblast growth factor–2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model

Abstract

A loss of neurons is observed in the hippocampus of many patients with epilepsies of temporal lobe origin. It has been hypothesized that damage limitation or repair, for example using neurotrophic factors (NTFs), may prevent the transformation of a normal tissue into epileptic (epileptogenesis). Here, we used viral vectors to locally supplement two NTFs, fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF), when epileptogenic damage was already in place. These vectors were first characterized in vitro, where they increased proliferation of neural progenitors and favored their differentiation into neurons, and they were then tested in a model of status epilepticus-induced neurodegeneration and epileptogenesis. When injected in a lesioned hippocampus, FGF-2/BDNF expressing vectors increased neuronogenesis, embanked neuronal damage, and reduced epileptogenesis. It is concluded that reduction of damage reduces epileptogenesis and that supplementing specific NTFs in lesion areas represents a new approach to the therapy of neuronal damage and of its consequences.epilepsy ͉ gene therapy ͉ neurotrophic factors

Enhancement of GABA A -current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy

“…A parallel development was observed in the hippocampus. Degenerating cells were observed in CA1, CA3, and in the hilus of the dentate gyrus, reminiscent of hippocampal sclerosis (18). As for the neocortex, this pattern of damage was clearly detectable at 24 h, peaked during latency and was already subsiding at the time of the first seizure, becoming undetectable 1 and 2 months after SE ( Fig.…”

“…Video-EEG recordings were performed as previously described (18). See SI Materials and Methods for further information.…”

“…All antibodies were incubated overnight, except those for GABA A receptor subunits that were incubated for 3 days. The number of GFAP-and NeuN-positive cells was counted in 1,392 × 1,040 frames in various hippocampal subareas, as previously described (18). Statistical analysis was performed using ANOVA and post hoc Newman-Keuls test.…”

“…Immunofluorescence was performed as previously described (18). The primary antibodies were as follows: MAP2abc (mouse monoclonal, Immunological Sciences) and GFAP (rabbit polyclonal, Sigma) 1:25 and 1:50, respectively; NeuN (mouse monoclonal, Chemicon) 1:100; GFAP (as above) 1:50; MAP2abc (as above) and GABA A α1 receptor subunit [rabbit polyclonal (39,40)] 1:25 and 1:50, respectively; parvalbumin (mouse monoclonal, Swant) and GABA A α1 receptor subunit (as above) both 1:50; GFAP (mouse monoclonal, Sigma) and GABA A α1 receptor subunit (as above) both 1:50; MAP2abc (as above) and GABA A α4 receptor subunit [rabbit polyclonal (39,40)] 1:25 and 1:50, respectively; NeuN (as above) and GABA A α4 receptor subunit (as above) 1:100 and 1:50, respectively; GFAP (mouse monoclonal, Sigma) and GABA A α4 receptor subunit (as above) both 1:50.…”

Compensatory Neurogenesis in the Injured Adult Brain

“…Administration of neurotrophic factors is r e l e v a n t a s m a n y f a c t o r s t h a t p r o m o t e neurogenesis (e.g: BDNF, FGF-2, IGF-1) are reduced in chronic epilepsy . Supporting this, a range of studies have demonstrated that administration of neurotrophic factors to both the normal and injured adult rodent brain can enhance hippocampal neurogenesis (Lichtenwalner, et al, 2001, Yoshimura, et al, 2001, Scharfman, et al, 2005, Rai, et al, 2007, Paradiso, et al, 2009, Paradiso, et al, 2011. Performing physical exercise and environmental enrichment have also been shown to enhance hippocampal neurogenesis, potentially through increased expression of a range of mitogenic factors such as BDNF, FGF2, NGF, IGF-1 and VEGF as well as phosphorylation of cAMP-response binding protein (CREB) (Nithianantharajah, et al, 2006, Van Praag, 2008, Llorens-Martín, et al, 2009, Lafenetre, et al, 2011 and may provide an appealing noninvasive therapeutic approach for the treatment of chronic TLE (Dhanushkodi, et al, 2008, Arida, et al, 2009.…”