Neuroprotective actions of Selegiline in inhibiting 1-methyl, 4-phenyl, pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons.
We have examined mitochondrial membranes and molecular hallmarks of apoptosis in response to increasing concentrations of 1-Methyl, 4-phenyl, Pyridinium ion (MPP(+)) in SK-N-SH neurons and have evaluated the neuroprotective potential of Selegiline with a primary objective to explore its mechanism(s) of neuroprotection. MPP(+)-induced apoptosis was characterized by spherical appearance, suppressed neuritogenesis, phosphatidyl serine externalization, plasma membrane perforations, mitochondrial membrane potential (Delta Psi) collapse, mitochondrial aggregation, and nuclear DNA fragmentation and condensation. At lower concentrations, MPP(+) (10-100 microM) produced mitochondrial swelling and loss of cristae, and at higher concentrations (300-500 microM), degeneration and aggregation of mitochondrial membranes in the peri-nuclear region, which were attenuated by Selegiline (10-50 microM) pre-treatment. At still higher concentrations, MPP(+) (>500 microM) produced necrotic changes represented by mitochondrial and plasma membrane ballooning and perforations. Selegiline provided partial neuroprotection at higher concentrations of MPP(+). MPP(+)-induced increases in reactive oxygen species, lipid peroxidation, cytochrome-C release, necrosis factor kappa-B (NF-kappa-B) activation, 8-hydroxy, 2 deoxy guanosine synthesis, alpha-synuclein indices, and reductions in glutathione, ATP, and superoxide dismutase were attenuated by Selegiline. Selegiline also attenuated MPP(+)-induced transcriptional activation of c-fos, c-jun, GAPDH, and caspase-3, suggesting that it may provide neuroprotection by preserving mitochondrial membranes, by attenuating molecular markers of apoptosis, by scavenging free radicals, and by regulating immediate early genes involved in neurodegeneration.
Sharma
Sushil K
SK
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, USA. skumar@medicine.nodak.edu
Carlson
Edward C
EC
Ebadi
Manuchair
M
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016501:Neurites / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010718:Phosphatidylserines / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology*
D005609:Free Radicals; D018696:Neuroprotective Agents; D010718:Phosphatidylserines; D012642:Selegiline; D015655:1-Methyl-4-phenylpyridinium