[Effect of selegiline against selective neurotoxins]

The complexity of the pharmacological activity of selegiline cannot be considered only as a result of a simple MAO-B inhibition. The mechanism of its neuroprotective action against the noradrenergic neurotoxin DSP-4 was widely studied (-)-p-fluoro-deprenyl (PFD), the chemical derivative of selegiline, with its possible metabolites were also involved into these studies. The results suggested that the uptake inhibitory effect of selegiline, and mainly that of its metabolite (-)-methylamphetamine (MA), played an essential role in the protection. MA was more potent to inhibit the uptake of noradrenaline and dopamine, than the parent compound. Neither selegiline nor its metabolite inhibited the reuptake of serotonin. In respect of the protection against DSP-4 induced toxicity PFD and its metabolites behaved similarly to selegiline, but their effects were more lasting than that of selegiline. After oral treatment selegiline undergoes an intensive "first pass" metabolism, which leads to an enhanced formation of MA. The better understanding of the fate of selegiline in the body, including its pharmacokinetic behaviour and metabolism, may contribute to a better knowledge of the complex pharmacological activity of the drug. The results could be summarised as follows. a) MAO-B inhibition-which is due to the parent compound-is an irreversible "hit and run" effect, the level of which after an initial phase is independent of the presence of the substance which caused it. b) The uptake inhibition is a reversible process and strictly proportional to the concentration of the substance responsible for the effect. In this respect the uptake inhibitory action of the metabolites exceeds that of the parent compounds. The role of the reversible uptake inhibition in neuroprotection may partly explain the need of the daily administration of selegiline to parkinsonian patients in spite of the irreversible MAO-B inhibitory action of the drug.