Protection of cultured dopamine neurons from MPP(+) requires a combination of neurotrophic factors.
Parkinson's disease is a progressive neurodegenerative disorder, caused in part by the loss of dopamine (DA) neurons in the substantia nigra (SN). Neurotrophic factors have been shown to increase the basal survival of DA neurons in vitro, as well as to protect the neurons from some toxins under certain in vitro conditions and in animal models. Although these factors have often been tested individually, they have rarely been studied in combinations. We therefore examined the effect of such combinations after acute exposure to the toxin 1-methyl-4-phenylpyridinium (MPP(+) ) using dissociated postnatal rat midbrain cultures isolated from SN and ventral tegmental area (VTA). We found that significant loss of DA neurons in the SN occurred with an LC50 of between 1 and 10 μm, whereas the LC50 of DA neurons from the VTA was approximately 1000-fold higher. We did not observe neuroprotection against MPP(+) by individual exposure to glial cell-line derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), transforming growth factor beta (TGFβ), basic fibroblast growth factor (FGF-2) or growth/differentiation factor 5 (GDF5) at concentrations of 100 or 500 ng/mL. Combinations of two, three or four neurotrophic factors were also ineffective. However, when the SN cultures were exposed to a combination of all five neurotrophic factors, each at a concentration of 100 ng/mL, we observed a 30% increase in DA neuron survival in the presence of 10 and 500 μm MPP(+) . These results may be relevant to the use of neurotrophic factors as therapeutic treatments for Parkinson's disease.
Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.|Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Juliann D
JD
Jaumotte
Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.|Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Stephanie L
SL
Wyrostek
Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.|Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Michael J
MJ
Zigmond
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D005260:Female; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D015655:1-Methyl-4-phenylpyridinium
BDNF; FGF2; GDF5; GDNF; Parkinson's disease; TGFβ