Local protective effects of nerve growth factor-secreting fibroblasts against excitotoxic lesions in the rat striatum.
Neurotrophic factors, such as nerve growth factor (NGF), in addition to their role in neuronal development, have protective effects on neuronal survival. Intracerebral implantation of cells genetically altered to secrete high levels of NGF is also found to promote neuronal survival in experimental lesioning models of the brain. The range of activity for such biological delivery systems has not yet been well described either spatially or temporally. Therefore, the authors chose to study the local and distant protective effects of an NGF-secreting rat fibroblast cell line implanted in an excitotoxic lesion model of Huntington's disease. They found that preimplantation of NGF-secreting fibroblasts placed within the corpus callosum reduced the maximum cross-sectional area of a subsequent excitotoxic lesion in the ipsilateral striatum by 80% when compared to the effects of a non-NGF-secreting fibroblast graft, and by 83% when compared to excitotoxic lesions in ungrafted animals (p < 0.003). However, NGF-secreting cells placed in the contralateral corpus callosum failed to affect striatal lesion size significantly when compared to contralateral or ipsilateral non-NGF-secreting cell implants. Of note, fibroblasts were clearly visible within the graft site at 7 and 18 days after implantation; however, few cells within the grafts stained positively for NGF peptide or for the messenger ribonucleic acid (mRNA) encoding the transfected NGF gene-construct at either time point. These results show that biological delivery systems for NGF appear to have a profound but local effect on neuronal excitotoxicity, which will necessitate careful neurosurgical placement for maximum effect. Furthermore, the ability of this genetically altered cell line to synthesize NGF mRNA and peptide appears to decrease spontaneously in vivo, a characteristic that will need to be addressed before this method of biological delivery can be utilized as a treatment for chronic degenerative diseases.
Frim
D M
DM
Neuroregeneration Laboratory, McLean Hospital, Belmont, Massachusetts.
Short
M P
MP
Rosenberg
W S
WS
Simpson
J
J
Breakefield
X O
XO
Isacson
O
O
D000818:Animals; D003337:Corpus Callosum / Q000503:physiopathology*; D003342:Corpus Striatum / Q000473:pathology; D005347:Fibroblasts / Q000502:physiology* / Q000637:transplantation; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D017378:Quinolinic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D009414:Nerve Growth Factors; D017378:Quinolinic Acid