Author:

Keywords:

neurospheres, transplantation, substantia nigra, gfp, dopaminergic, rescue, neural stem-cells, fibroblast-growth-factor, central-nervous-system, unbiased stereological estimation, rat substantia-nigra, partial lesion model, parkinsons-disease, neurotrophic factor, progenitor cells, 6-hydroxydopamine lesion, Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, GFP, NEURAL STEM-CELLS, FIBROBLAST-GROWTH-FACTOR, CENTRAL-NERVOUS-SYSTEM, UNBIASED STEREOLOGICAL ESTIMATION, RAT SUBSTANTIA-NIGRA, PARTIAL LESION MODEL, PARKINSONS-DISEASE, NEUROTROPHIC FACTOR, PROGENITOR CELLS, 6-HYDROXYDOPAMINE LESION, Amphetamine, Animals, Cell Survival, Cell Transplantation, Cells, Cultured, Central Nervous System Stimulants, Coculture Techniques, Culture Media, Conditioned, Culture Media, Serum-Free, Dopamine, Female, Hydroxydopamines, Immunohistochemistry, Mesencephalon, Mice, Mice, Inbred C57BL, Neostriatum, Neurons, Pregnancy, RNA, Reverse Transcriptase Polymerase Chain Reaction, Stereotyped Behavior, Substantia Nigra, Tyrosine 3-Monooxygenase, 1109 Neurosciences, 1701 Psychology, 1702 Cognitive Sciences, Neurology & Neurosurgery, 3209 Neurosciences, 5202 Biological psychology

Abstract:

The pathogenesis of Parkinson's disease (PD) involves ongoing apoptotic loss of dopaminergic neurons in the substantia nigra pars compacta. Local delivery of the trophic factors can rescue dopaminergic neurons and halt the progression of PD. In this study we show that fetal E11 striatum-derived neurospheres and E14.5 ventral mesencephalon (VM) -derived neurospheres (NSE11 and NSvm, respectively) are a source of factors that rescue dopaminergic neurons. First, long-term expanded NSE11 and NSvm rescued primary dopaminergic neurons from serum-deprivation induced apoptosis and promoted survival of dopaminergic neurons for 14 days in vitro and this effect was due to soluble contact-independent factor/s. Second, green fluorescent protein-expressing NSE11 and NSvm grafted into the midbrain of mice with unilateral 6-hydroxydopamine-induced Parkinsonism resulted in partial rescue of the nigro-striatal system and improvement of the hypo-dopaminergic behavioral deficit. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that intact NSE11 and NSvm expressed fibroblast growth factor-2, brain-derived neurotrophic factor (BDNF), pleiotrophin, neurotrophin-3, but not glial cell line-derived neurotrophic factor (GDNF). GDNF expression was also undetectable in vivo in grafted NSE11 and NSvm suggesting that NS-derived factor/s other than GDNF mediated the rescue of nigral dopaminergic neurons. Identification of NS-derived soluble factor(s) may lead to development of novel neuroprotective therapies for PD. An unexpected observation of the present study was the detection of the ectopic host-derived tyrosine hydroxylase (TH) -expressing cells in sham-grafted mice and NSE11- and NSvm -grafted mice. We speculate that injury-derived signals (such as inflammatory cytokines that are commonly released during transplantation) induce TH expression in susceptible cells. Crown Copyright (C) 2008 Published by Elsevier Ltd on behalf of IBRO. All rights reserved.