Neuroprotection by propargylamines in Parkinson's disease: intracellular mechanism underlying the anti-apoptotic function and search for clinical markers.
In Parkinson's and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (-)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-kappaB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.
Naoi
M
M
Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan. mnaoi@giib.or.jp
Maruyama
W
W
Yi
H
H
Akao
Y
Y
Yamaoka
Y
Y
Shamoto-Nagai
M
M
D000480:Alkynes / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D011437:Propylamines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012642:Selegiline / Q000494:pharmacology*
D000480:Alkynes; D005819:Genetic Markers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007189:Indans; C402679:N-2-heptyl-N-methylpropargylamine; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011437:Propylamines; D019253:Proto-Oncogene Proteins c-bcl-2; C031967:rasagiline; C009054:propargylamine; D012642:Selegiline; D010293:Pargyline