Selegiline can mediate neuronal rescue rather than neuronal protection.
Selegiline [(-)-deprenyl] has been reported to slow the progression of disabling deficits in Parkinson's disease (PD) and cognitive decline in Alzheimer disease (AD). The apparent slowing has been proposed to be based on either symptomatic improvement due to increased dopaminergic neurotransmission or alternately on protection of neurons from damage caused by toxic oxidative radicals. Both mechanisms are hypothesized to result from the inhibition of monoamine oxidase type B (MAO-B) activity. Our experiments in two animal models have shown that selegiline has a second, previously unsuspected action. That is, selegiline can rescue neurons after they have sustained lethal damage and the rescue is independent of MAO-B inhibition. It was previously shown that the coadministration of selegiline with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could protect dopaminergic substantia nigra neurons (dSNns) from damage by blocking conversion of MPTP to its active radical N-methyl-4-phenylpyridinium (MPP+) by inhibiting MAO-B. In the first model, we treated C57BL mice with MPTP but delayed selegiline treatment for 72 h after the MPTP treatment to allow for complete conversion of MPTP to MPP+ and for maximal dSNn damage by MPP+. The delayed selegiline treatment rescued approximately 69% of the dSNns that had not died by the time the treatment began but were found to die with saline treatment. Selegiline doses that were too small to cause inhibition of MAO-B substrate oxidation rescued the MPTP-damaged dSNns. The second model was based on previous work showing that immature (14-day-old) rat facial motoneurons die after axotomy because of a loss of trophic support from the muscle they innervate. Selegiline treatment increased the number of motoneurons surviving axotomy from 24 to 52%, showing that selegiline can rescue neurons by partially compensating for the loss of target-derived trophic support. This "trophic-like" action of selegiline might account for the reported slowing of the progression of PD and AD and suggests that selegiline therapy may be of value with acute nervous system damage, particularly damage caused by trauma.
Tatton
W G
WG
Center for Research in Neurodegenerative Diseases, University of Toronto, Canada.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D004298:Dopamine / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008995:Monoamine Oxidase / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000187:drug effects* / Q000502:physiology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology*; D012642:Selegiline / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology
D007527:Isoenzymes; D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D004298:Dopamine