Introduction
Studies with (-)-deprenyl (selegiline) revealed that it cannot be considered as a simple monoamine oxidase type-B (MAO-B) inhibitor, because its pharmacological activity is rather complex (1). The dopamine sparing activity as well as the neuroprotective and neuronal rescue effect of selegiline in the central nervous system (CNS) cannot be explained solely by its irreversible enzyme inhibitory action. Its inhibition on the biogenic amine reuptake may also play a role in the complex pharmacological activity of the drug. Mammalian neurones are post mitotic and when damaged, they cannot be regenerated or replaced. Thus pathological processes causing neuronal loss generally have irreversible consequences. Because of this, the territory appears to be rather unpromising for pharmacological interventions, except for the particular case of Parkinson’s disease (PD). There are different cellular processes which underlie neuronal loss causing neuronal dysfunction. These are neuronal necrosis and apoptosis. Selegiline could reduce neuronal death by several mechanisms.
Neuroprotective effect of selegiline
Protection induced by selegiline treatment may derive partly from the decreased levels of toxic radicals that escape from the astrocytes in sufficient concentrations to produce lipid peroxidation of nearby neuronal membranes. By inhibiting MAO-B in the CNS selegiline treatment may decrease the free radical formation (generation of H2O2) from the normal metabolism of biogenic amines, mainly dopamine. Hydrogen peroxide oxidises Fe2+ ion and generates hydroxyl radicals by the metal-catalysed Haber-Weiss reaction. MAO-B activity increases with age and the over-production of H2O2 may contribute to the neuronal damage. Thus, the inhibition of the age dependent increase of MAO-B activity by selegiline treatment may also be protective. It was published recently that a decrease in radical formation could be induced with (-)-deprenyl concentrations  as  low  as 10-11 M, too small to inhibit MAO-B, showing that (-)-deprenyl  can  reduce oxidative radical levels by a mechanism other than MAO-B inhibition. Selegiline treatment may also increase the free radical scavenging capacity of the brain by an elevation of superoxide dismutase (SOD) activity. As a consequence of MAO-B inhibition, selegiline treatment may also prevent the activation of the environmental pre-toxins. Due to its uptake inhibitory properties it can prevent the selective uptake of neurotoxins into the nerve endings, thereby obviating the neuronal damage. As far as the inhibition of biogenic amine uptake is concerned, the metabolites of selegiline [(-)-methylamphetamine and (-)-amphetamine] are more potent, than the parent compound.
Birkmayer and his colleagues were the first who have indicated the neuroprotective effect of selegiline based on a retrospective evaluation of seven year long clinical application of the drug in PD. A prospective randomised, placebo-controlled trial has also been performed (DATATOP) to test the hypothesis that deprenyl provides neuroprotective therapy in PD. These studies showed that selegiline significantly delayed the onset of disability necessitating levodopa treatment. DATATOP study demonstrated that selegiline treatment has symptomatic effect that could mask rather than prevent neuronal degeneration. Several mechanisms may could account for the symptomatic effects detected in patients treated with selegiline. These include: 1. increased striatal dopamine content 2. increased level of trace amines like phenylethylamine, which can elicit dopaminergic effect 3. amphetamine metabolites formed from selegiline which can inhibit the uptake and promote the release of dopamine. 4. the treatment can up-regulate the cellular defence mechanisms which can lead to cell recovery (2).
Selegiline treatment in Alzheimer’s disease (AD) is proposed by several observations. PD and AD are linked in many aspects. MAO-B activity is also increased in AD, compared to age matched control. A number of studies have shown that chronic selegiline treatment resulted in a mild improvement in cognitive functions in AD (3).
Neuronal rescue effect of selegiline
It has become apparent that selegiline administration following the toxic insults can rescue the damaged neurones. It has also been shown that (-)-deprenyl increased the neuronal survival of PC12 cells in tissue culture. The withdrawal of serum and nerve growth factor induced apoptosis in PC12 cells, but (-)-deprenyl inhibited the programmed cell death in a concentration of less than 10-9 M. This rescue effect of (-)-deprenyl was independent of its MAO-B inhibition. The (+)-enantiomer of deprenyl lacks this property (4).
 In order to study the neuronal rescuing effect of (-)-deprenyl we used M-1 human melanoma cell culture in our laboratory. Apoptosis was elicited by serum deprivation, and deprenyl was tested to prevent the programmed cell death.

Table 1. The effect of (-)-  and (+)-deprenyl on apoptosis of M-1 cell cultures
(Apoptotic index %)
 
 

 The ratio of apoptotic cells increased gradually in the untreated cell cultures from the 24th to 72nd hours after serum withdrawal (Table 1). At 72 hours  practically  only  apoptotic  cells  and  cell  debris  were found. (-)-deprenyl treatment significantly decreased the number of apoptotic cells even in its lowest concentration. At 72 hours the cultures appeared to be viable. However, (+)-deprenyl did not prevent the high incidence of apoptosis (5).
Summary
Selegiline treatment is able to increase the dopaminergic tone in the CNS by several mechanisms. It inhibits the metabolic degradation of dopamine. In addition, the metabolites formed  from selegiline reduce the uptake and promote the release of the transmitter. The age related increase in MAO-B activity can also be blocked by selegiline administration, which can decrease the resulting oxidative damage of the CNS. Selegiline pre-treatment can inhibit the formation of toxins from pre-toxins and their uptake into the nerve endings. In small doses selegiline is also effective in post-treatment schedule, having neuronal rescue effect, which can partly be due to the inhibition of apoptosis of the neurones by the drug. Selegiline is still the most widely used MAO inhibitor in the treatment of PD. It is administered alone or in combination with levodopa. The treatment can postpone the need for levodopa or potentiate its effect. The usage of selegiline treatment in AD is less frequent than in PD, but some results indicate a mild improvement in cognitive functions of the patients.
References
1. Magyar K.. In: Inhibitors of monoamine oxidase B. Ed.: Szelenyi I, Birkhauser Verlag, Basel  1992;125-143.
2. Olanow CW. J Neural Transm [Suppl] 1996;48:75-84.
3. Berry MD. et al., Neurobiology 1994;44:141-161.
4. Tatton WG. et al., J Neurochem  1994;63:1572-1575
5. Magyar K. et al., J Neural Transm [Suppl] 1997;52:115-129.