Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF.
Consistent with the notion that a defect in cellular energy metabolism is a cause of human neurodegenerative disease, systemic treatment with the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA) can model the striatal neurodegeneration seen in Huntington's disease. Previously, we have found that nerve growth factor (NGF), delivered biologically by the implantation of a genetically altered fibroblast cell-line, can protect locally against striatal degeneration induced by infusions of high doses of glutamate receptor agonists. We now report that implantation of NGF-secreting fibroblasts reduces the size of adjacent striatal 3-NPA lesions by an average of 64%. We conclude that biologically delivered NGF protects neurons against excitotoxicity and mitochondrial blockade--both energy-depleting processes--implying that appropriate neurotrophic support in the adult brain could protect against neurodegenerative diseases caused in part by energy depletion.
Frim
D M
DM
Neuroregeneration Laboratory, McLean Hospital, Belmont, Massachusetts 02178.
Simpson
J
J
Uhler
T A
TA
Short
M P
MP
Bossi
S R
SR
Breakefield
X O
XO
Isacson
O
O
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D016380:Brain Tissue Transplantation / Q000502:physiology; D002460:Cell Line; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects* / Q000648:ultrastructure; D004734:Energy Metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005818:Genetic Engineering; D007150:Immunohistochemistry; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D009410:Nerve Degeneration / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D009414:Nerve Growth Factors; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D014446:Tyrosine 3-Monooxygenase; D000110:Acetylcholinesterase; C015392:3-nitropropionic acid