New horizons in molecular mechanisms underlying Parkinson's disease and in our understanding of the neuroprotective effects of selegiline.
There have been many claims that the selective monoamine oxidase type B (MAO-B) inhibitor selegiline may have distinct properties in slowing the progression of Parkinson's disease (PD). Degeneration of nigro-striatal dopaminergic neurons is the primary histopathological feature of PD. Although many different hypotheses have been advanced, the cause of chronic nigral cell death and the underlying mechanisms remain elusive as yet. Therefore, there is no clear knowledge regarding an understanding of the reported effects of selegiline on the progression of PD. However, there is a considerable body of indirect evidence that oxidative stress may play a role in the pathogenesis of this illness. Oxidative stress refers to cytotoxic consequences of hydrogen peroxide and oxygen-derived free radicals such as the hydroxyl radical (.OH), the superoxide anion (.O2), and nitric oxide (NO), which are generated as byproducts of normal and aberrant metabolic processes that utilize molecular oxygen. On the other hand, an increasing body of experimental data has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurological disease. One of the receptor which is particularly involved in the toxic effects of excitatory amino acids is the NMDA (N-methyl-D-aspartate) receptor. Excessive stimulation of this type of receptor by glutamic acid or NMDA agonists leads to a massive influx of calcium ions into the neuron followed by activation of a variety of calcium-dependent enzymes, impaired mitochondrial function, and the generation of free radicals. This article will consider the concept that excitotoxicity is linked with the generation of free radicals. In view of this idea it will be further discussed how selegiline might exert its neuroprotective effects via indirect actions on the polyamine binding site of the NMDA receptor. Under treatment with the MAO-B inhibitor selegiline, the degradation of putrescine via MAO, a key factor in regulating the polyamine metabolism, might be diminished in the Parkinsonian brain, which in turn would suppress the polyamine synthesis. Hence, the reported neuroprotective effect of selegiline might also receive a contribution from the diminished potentiation of the NMDA receptor by the polyamine binding site. On the other hand, since N1-acetylated spermine and spermidine are also good substrates of MAO-B, it is likely that these compounds will be present in the brain in increased concentrations. It therefore seems possible that they will exert a neuroprotective effect via an antagonistic modulation of the polyamine binding site of the NMDA receptor.
Gerlach
M
M
Neurologische Klinik, Ruhr-Universität Bochum, Germany.
Desser
H
H
Youdim
M B
MB
Riederer
P
P
D001665:Binding Sites / Q000187:drug effects; D002986:Clinical Trials as Topic; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009498:Neurotoxins / Q000009:adverse effects; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011073:Polyamines / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D012642:Selegiline / Q000494:pharmacology / Q000627:therapeutic use*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018697:Nootropic Agents; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D012642:Selegiline; D005680:gamma-Aminobutyric Acid; D008995:Monoamine Oxidase