Implanted NGF-producing fibroblasts induce catalase and modify ATP levels but do not affect glutamate receptor binding or NMDA receptor expression in the rat striatum.
Neurotrophic factors, in particular NGF, have been shown to potently protect against glutamate-receptor-mediated toxicity. In order to further investigate the mechanism of this protection, we investigated the in vivo effects of fibroblasts, genetically modified to secrete NGF and implanted near the striatum, on striatal excitatory amino acid binding and receptor expression, on the induction of the peroxidative enzyme catalase, and on cellular energy metabolism in the striatum. Seven days after implantation into the corpus callosum of either a genetically altered NGF-producing (NGF[+]) or unaltered parental (NGF[-]) fibroblast cell-line, there is a time point at which NGF[+] cells have been shown to prevent excitotoxic insults. At that time point after implantation, we found that NGF[+] grafts caused a marked increase in catalase mRNA expression in and around the NGF[+] grafts. The NGF[+] grafts also reduced basal levels of striatal ATP when compared to the effects of NGF[-] grafts. No changes were observed in [3H]glutamate binding and NMDA receptor mRNA expression. We conclude that effects of NGF[+] fibroblast grafts on glutamate receptor mediated toxicity are not by direct effects on glutamate receptors or glutamate binding, but rather appear to be a process involving enzymatic induction and modification of cellular energy stores. The observed increase in catalase mRNA suggests that peroxidative metabolism may be involved in these NGF-mediated effects.
Frim
D M
DM
Neurology Service, Massachusetts General Hospital, Boston.
Wüllner
U
U
Beal
M F
MF
Isacson
O
O
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002374:Catalase / Q000378:metabolism*; D017690:Cell Transplantation; D003342:Corpus Striatum / Q000378:metabolism*; D004790:Enzyme Induction; D005347:Fibroblasts / Q000378:metabolism* / Q000637:transplantation*; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism*; D015345:Oligonucleotide Probes / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D009414:Nerve Growth Factors; D015345:Oligonucleotide Probes; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000255:Adenosine Triphosphate; D002374:Catalase