Different patterns of induction of fibroblast growth factor-2 and brain-derived neurotrophic factor messenger RNAs during kindling epileptogenesis, and development of a herpes simplex vector for fibroblast growth factor-2 gene transfer in vivo.

Abstract

To investigate the gene expression patterns of brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF-2) in the kindling model, and to construct a replication-defective herpes simplex virus vector to induce expression of FGF-2 in vivo. RNase protection assay and herpes simplex virus vector (TH FGF-2) deleted in the immediate-early genes ICP4, ICP22, and ICP27, with FGF-2 inserted in tk under the control of the human cytomegalovirus immediate-early promoter. A single kindling stimulation did not modify BDNF gene expression, whereas it increased FGF-2 messenger RNA (mRNA) levels in the hippocampus, the cortex, and the hypothalamus. BDNF and FGF-2 gene expression were not altered in kindled animals left unstimulated for 1 week. In contrast, kindled seizures produced a great increase in hippocampal and cortical BDNF mRNA levels, but FGF-2 mRNA was increased only in the ipsilateral cortex. Infection of Vero cells with TH FGF-2 resulted in a long-lasting increase in FGF-2 levels. Protein extracts of infected cells induced neuronal differentiation of PC12 cells, indicating that the newly synthesized FGF-2 was biologically active. Robust transient transgene expression was observed in the rat hippocampus after inoculation with TH FGF-2 in the absence of significant toxicity. BDNF and FGF-2 are recruited at different stages of kindling and, accordingly, may play different roles in the adaptive changes taking place during epileptogenesis. TH FGF-2 is suitable for studies of FGF-2 involvement in kindling epileptogenesis.