PMID- 8197193
OWN - NLM
STAT- MEDLINE
DCOM- 19940627
LR  - 20220409
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 91
IP  - 11
DP  - 1994 May 24
TI  - Implanted fibroblasts genetically engineered to produce brain-derived 
      neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic 
      neurons in the rat.
PG  - 5104-8
AB  - The trophism of brain-derived neurotrophic factor (BDNF) for dopaminergic cells 
      in culture has led to significant interest in the role of BDNF in the etiology 
      and potential treatment of Parkinson disease. Previous in vivo investigation of 
      BDNF delivery to axotomized substantia nigra dopaminergic neurons in the adult 
      rat has shown no protective effect. In this study, we produced nigral 
      degeneration by infusing 1-methyl-4-phenylpyridinium (MPP+), a mitochondrial 
      complex I inhibitor and the active metabolite of 1-methyl-4-phenyl-1,2,3,6- 
      tetrahydropyridine (MPTP), into the rat striatum. The subsequent loss of nigral 
      neurons was presumably due to mitochondrial toxicity after MPP+ uptake and 
      retrograde transport to the substantia nigra. We engineered immortalized rat 
      fibroblasts to secrete human BDNF and implanted these cells near the substantia 
      nigra 7 days before striatal MPP+ infusion. We found that BDNF-secreting 
      fibroblasts markedly increased nigral dopaminergic neuronal survival when 
      compared to control fibroblast implants. The observation that BDNF prevents 
      MPTP-induced dopaminergic neuronal degeneration in the adult brain has 
      significance for the treatment of neurodegenerative disorders, which may involve 
      mitochondrial dysfunction, such as Parkinson disease.
FAU - Frim, D M
AU  - Frim DM
AD  - Neuroregeneration Laboratory, McLean Hospital, Belmont, MA 02178.
FAU - Uhler, T A
AU  - Uhler TA
FAU - Galpern, W R
AU  - Galpern WR
FAU - Beal, M F
AU  - Beal MF
FAU - Breakefield, X O
AU  - Breakefield XO
FAU - Isacson, O
AU  - Isacson O
LA  - eng
GR  - NS 24279/NS/NINDS NIH HHS/United States
GR  - NS 29178/NS/NINDS NIH HHS/United States
GR  - NS 30064/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Receptors, Dopamine)
RN  - R865A5OY8J (1-Methyl-4-phenylpyridinium)
SB  - IM
MH  - 1-Methyl-4-phenylpyridinium/antagonists & inhibitors/*toxicity
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor
MH  - Cell Line
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Fibroblasts/metabolism/*transplantation
MH  - Genetic Engineering
MH  - Male
MH  - Nerve Degeneration
MH  - Nerve Growth Factors/*genetics/pharmacology
MH  - Nerve Tissue Proteins/*genetics/pharmacology
MH  - Neurons/*drug effects/metabolism/pathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Dopamine/drug effects/metabolism
MH  - Substantia Nigra/drug effects/metabolism
PMC - PMC43940
EDAT- 1994/05/24 00:00
MHDA- 1994/05/24 00:01
PMCR- 1994/11/24
CRDT- 1994/05/24 00:00
PHST- 1994/05/24 00:00 [pubmed]
PHST- 1994/05/24 00:01 [medline]
PHST- 1994/05/24 00:00 [entrez]
PHST- 1994/11/24 00:00 [pmc-release]
AID - 10.1073/pnas.91.11.5104 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1994 May 24;91(11):5104-8. doi: 
      10.1073/pnas.91.11.5104.