[Molecular mechanisms of the neuroprotective effect of (-)-deprenyl].
(-)-Deprenyl, the irreversible inhibitor of monoamine oxidase B, has been used for decades in the therapy of Parkinson's disease. It improves parkinsonian symptoms due to its dopamine potentiating and antioxidant properties and presumedly delays disease progression. Its complex pharmacological action cannot be explained solely by its monoamine oxidase B inhibitory property. Recently, (-)-deprenyl has been demonstrated to exert antiapoptotic, neuroprotective effects on a number of in vitro and in vivo models in a dose significantly lower than required for monoamine oxidase B inhibition. (-)-Deprenyl and related propargylamines prevent apoptotic cell death by preserving the integrity of the mitochondrion that may be based on the activation of a complex transcriptional program. The changes in gene expression initiated by propargylamines incited to search for further possible target molecules that would explain more accurately the antiapoptotic effect of these compounds. The latest molecular targets include such classical metabolic enzymes, the homologues of which may participate in the regulation of gene expression as a part of transcriptional factor complexes. Some of the propargylamine targets--glyceraldehyde-3-phosphate dehydrogenase, poly(ADP-ribose) polymerase, nuclear amine oxidases--have already been demonstrated to be capable of transforming the metabolic changes in the cell to transcriptional responses. Data are accumulating about the relationship of these enzymes and propargyl compounds, but the real significance of this issue will only be established by future research.
Pálfi
Melinda
M
Magyar Tudományos Akadémia, Neurokémiai Kutatócsoport, Budapest. melinda.palfi@net.sote.hu
Szökó
Eva
E
Kálmán
Magyar
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010293:Pargyline / Q000031:analogs & derivatives / Q000378:metabolism; D010770:Phosphotransferases / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology* / Q000627:therapeutic use
D000975:Antioxidants; D000978:Antiparkinson Agents; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011437:Propylamines; C009054:propargylamine; D012642:Selegiline; D010293:Pargyline; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011065:Poly(ADP-ribose) Polymerases; D010770:Phosphotransferases; D004298:Dopamine