title: The neuroprotective and neuronal rescue effects of (-)-deprenyl.
abstract: The pharmacological effects of (-)-deprenyl is multi-fold in its nature (dopamine sparing activity, neuroprotective and neuronal rescue effects), which cannot be explained solely by the irreversible MAO-B inhibitory action of the substance. Deprenyl slightly inhibits the re-uptake of noradrenaline and dopamine, but methylamphetamine, the metabolite of the inhibitor, by one order of magnitude is more potent in this respect, than the parent compound. Neither the metabolite nor (-)-deprenyl acts on the uptake of serotonin. The inhibitor has an intensive first pass metabolism after oral treatment. The in vivo pharmacokinetic studies with (-)-deprenyl, using the double labelled radioisotope technique (1.5 mg/kg; orally) in rats revealed that the molar concentration of methylamphetamine can reach the level suitable to induce a significant inhibition of amine uptake. Deprenyl, but especially methylamphetamine pre-treatment can prevent the noradrenaline release induced by the noradrenergic neurotoxin DSP-4. The uptake inhibitory effect of (-)-deprenyl and the metabolites is reversible. After repeated administration of (-)-deprenyl (1.5 mg/kg daily, for 8 days) sustained concentration of its metabolites was detected, compared to that of the acute studies. This can at least partly explain why (-)deprenyl should be administered daily to evoke therapeutic effects in Parkinson's disease. Administration of (-)-deprenyl in a low dose, following the toxic insult, can rescue the damaged neurones. The neuronal rescue effect of the drug was studied on M-1 human melanoma cells in tissue culture. The inhibitor reduced the apoptosis of serum-deprived M-1 cells, but the (+)-isomer failed to exert this effect. The (+/-)-desmethyl-deprenyl almost lacks the property to inhibit apoptosis. For neuroprotection and neuronal rescue an optimal dose of (-)-deprenyl should be administered, because to reach a well balanced concentration of the metabolites in tissues is critical.
authors.affiliation: Department of Pharmacodynamics, Semmelweis University of Medicine, Budapest, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Magyar
authors.forename: B
authors.initials: B
authors.lastname: Szende
authors.forename: J
authors.initials: J
authors.lastname: Lengyel
authors.forename: J
authors.initials: J
authors.lastname: Tarczali
authors.forename: I
authors.initials: I
authors.lastname: Szatmáry
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001596:Benzylamines / Q000633:toxicity; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008545:Melanoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D012642:Selegiline / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000978:Antiparkinson Agents; D001596:Benzylamines; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012642:Selegiline; C012102:DSP 4