Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids.
With the exception of L-DOPA pharmacological treatment in Parkinson's disease, the neurodegenerative diseases lack effective treatment. Previous studies of neurodegenerative diseases suggest that symptoms arise secondary to defects in local neuronal circuitry and cannot be treated effectively with systemic drug delivery. Therefore, a promising treatment is the application of fetal or genetically engineering cells which protect or replace neurons in deficient regions. Engineered cells can be derived from cell lines or grown from recipient host fibroblasts or other cells, then modified to produce and secrete substances at a specific area of the brain. A previous study using parallel intracerebral infusions of nerve growth factor and an excitotoxic amino acid into the rat striatum demonstrated a protective effect of nerve growth factor on neurons [Aloe L. (1987) Biotechnology 5, 1085-1086]. In order to further test this paradigm, we have utilized a biological delivery system of nerve growth factor by implanting fibroblasts into the rat striatum which secrete high levels of nerve growth factor, prior to infusing the neurotoxins quinolinate or quisqualate. Animals in this group had smaller lesions than did a group implanted with a similar non-nerve growth factor-producing graft. In addition, marked neuronal sparing was noted within areas of lesions in those animals containing a nerve growth factor-producing graft. These results indicate that implantation of genetically engineered nerve growth factor-secreting cells can be used to protect neurons at a specific target from excitotoxin-induced lesions.
Schumacher
J M
JM
Neuroregeneration Laboratory, Harvard Medical School, Belmont, MA.
Short
M P
MP
Hyman
B T
BT
Breakefield
X O
XO
Isacson
O
O
D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D005818:Genetic Engineering; D006816:Huntington Disease; D008297:Male; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016318:Quisqualic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology
D009414:Nerve Growth Factors; D009498:Neurotoxins; D011805:Quinolinic Acids; D011993:Recombinant Fusion Proteins; D016318:Quisqualic Acid; D017378:Quinolinic Acid