Radical scavenging

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Fig. 1. The pathway of dopamine metabolism by monoamine oxidase and autoxidation and the its interaction with iron to induce oxidative stress induced neuronal death

OH HLA20

OH VK28

OH HLA20

r cooEt

OH

OH

M31

n

M26 D-isomer M29 L-isomer

OH OH M30B

OH M30A

Fmoc-

Fmoc-

M24 D-isomer M25 L-isomer

Fig. 2. Structures of brain permeable novel iron chelators derived from iron chelator VK-28 (Zheng et al., 2005)

OH OH M30B

M24 D-isomer M25 L-isomer

Et = CH2CH3

Fig. 2. Structures of brain permeable novel iron chelators derived from iron chelator VK-28 (Zheng et al., 2005)

hydrogen peroxide initiated generation of reactive OH' (Fenton chemistry), secondly they might mobilize out chelatable iron from the brain and thirdly they prevent the autoxidation of dopamine to cytotoxic semiquinone, with the resultant liberation of oxygen radicals. On several occasions dopamine metabolism via autoxidation and by the reaction of MAO has been implicated to induce degeneration of nigrostriatal dopamine neurons (Riederer et al., 1989; Paris et al., 2005) (Fig. 1). Such a hypothesis is not far fetched, since D-penicillamine, a copper chelator, has been successfully employed in the treatment of Wilson disease for removal of neuronal copper. Aceruloplasminemia is a neurodegen-erative disease associated with increased deposition of iron in the globus pallidus and substantia nigra. A recent study has shown that chronic desferal given in relatively large doses resulted in a decrease in iron in both regions, as shown by MRI, which correlated with clinical improvements (Miyajima et al., 1997). A recent report has shown that chelat-able iron is a potent releaser of excitotoxic glutamate, as a consequence of acotinase activation, which has consistently been implicat ed in the neurodegenerative diseases including PD and Alzheimer's disease (Mcgahan et al., 2005).

These previous studies, together with the fact that systemic injection of VK-28, unlike that of desferal, is brain permeable and neu-roprotective in the 6-OHDA and MPTP models. (Ben Shachar et al., 2004, Youdim et al., 2004b) led us to modify VK-28 by introducing the MAO-inhibitory-neuroprotective propargylamine moiety at different sites in the molecule. The result has been development of multifunctional neuroprotective M30 series of brain permeable iron chelators (Fig. 2). These compounds have similar iron chelating potency to desferal, possess potent irreversible brain selective MAO-AB inhibitory activity and neuroprotective and neurorescue properties similar to rasagiline (Youdim, 2005) as anti PD (Zheng et al., 2005a).

Iron chelating and antioxidant properties of multifunctional M30 derivative iron chelators

Several novel antioxidant-iron chelators bearing 8-hydroxyquinoline moiety were synthe sized, and various properties related to their iron chelation, and neuroprotective action were investigated (Zheng et al., 2005a, b) (Fig. 1). All the chelators including M30, M30A, M30B and HLA-20 exhibited strong iron(III) chelating and high antioxidant properties with ability to inhibit mitochondrial membrane lipid peroxidation. Chelator M30 and HLA20 had good permeability into K562 cells and displayed the highest protective effects against differentiated P19 cell death induced by 6-hydroxydopamine. EPR studies suggested that these chelators also act as radical scavenger to directly scavenge hydro-xyl radical (Zheng et al., 2005a, b).

In vitro MAO-A and B inhibitory activity of M30

These novel multifunctional chelators were further examined for their activity as antiox-idants, MAO-B inhibitors, and neuroprotective agents in vitro. Determination of Vk-28, desferal and a large number of iron and copper chelators indicated that these compounds do not inhibit MAO-A or B significantly in vitro (Youdim et al., 2004a; Zheng et al., 2005b). Three of the selected chelators possessing propargylamine moiety of rasagiline (M30, M30A and M30B and HLA20 and M32) were the most effective in inhibiting iron-dependent lipid peroxidation in rat brain mitochondrial homogenates with IC50 (12-16 mM) value comparable to that of desferal, a prototype iron chelator which does not cross the blood brain barrier. Their antioxidative activities were further confirmed using electron paramagnetic resonance spectroscopy, demonstrating similarity to desferal. In PC12 cell culture, the three above novel chelators at 0.1 mM were able to attenuate cell death induced by serum-deprivation and neurotoxicity induced by 6-hydroxydopamine and hydrogen peroxide. M30 possessing the N-propargyl MAO inhibitory moiety of the antiparkinson drug rasagiline displayed more neuroprotec-tive potency than that of rasagiline as did

N-propargyl piperazine chelator, HLA-20. In addition, the in vitro brain mitochondrial MAO assays showed that M30 was a highly potent MAO-A and B inhibitor (IC50, MAO-A, 0.037 ± 0.02; MAO-B, 0.057 ± 0.01), while M30A and M30B showed MAO-A and B inhibitory potency with one-two orders of magnitude less and HLA20 was a moderately selective MAO-B with IC50 of 110 mM. These data suggested that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for treatment of various neurodegenerative disorders including PD and AD.

In vivo MAO-A and B inhibitory activity and prevention of MPTP neurotoxicity

The examination of acute (1-5mg/kg) and chronic (5-10mg/kg) IP or PO once daily for 14 days) in vivo studies in mice and rats, have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor (Gal et al., 2005). It has little effects on the enzyme activities of the liver and small intestine. This is similar to what we have observed with our anti Alzheimer-antiparkinson drug ladostigil (TV3326) (Weinstock et al., 2000; Youdim and Buccfesco, 2005). Its N-desmethylated derivative, M30A and M30B are significantly less active in vivo, confirming the in vitro results. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum, hippocampus and hypothalamus. In the MPTP (N-methyl-4-phenyl-1,2,3,6-tet-rahydropyridine) mouse model of Parkinson's disease it attenuates the dopamine depleting action of the neurotoxin, the loss in tyrosine hy-droxylase activity and increases striatal levels of dopamine, serotonin and noradrenaline, while decreasing their metabolites (Fig. 3a, b). Since dopamine is equally well metabolized

"3 60

Tyrosine hydroxylase activity

Tyrosine hydroxylase activity

"3 60

control

M30 MPTP

M30+MPTP

*p<0.05 vs. MPTP, #p<0.05 vs. control control M30 MPTP M30+MPTP

Fig. 3. Neuroprotective effect of M30, an iron chelator-brain selective monoamine oxidase-AB inhibitor in MPTP mouse model of Parkinsonism (Zheng et al., 2005; Gal et al., 2005)

control

M30 MPTP

M30+MPTP

*p<0.05 vs. MPTP, #p<0.05 vs. control control M30 MPTP M30+MPTP

Fig. 3. Neuroprotective effect of M30, an iron chelator-brain selective monoamine oxidase-AB inhibitor in MPTP mouse model of Parkinsonism (Zheng et al., 2005; Gal et al., 2005)

by MAO-A and -B, it is expected that M30 would have a greater dopamine neurotransmission potentiation in Parkinson's disease. This is important since selective MAO-A (clorgyline, moclobemide) or MAO-B (sele-giline, rasagiline lazabemide) inhibitors do not alter brain dopamine. Only when both forms are inhibited does brain dopamine increase.

The importance of iron chelation and MAO-A and B inhibition by M30

for dopamine neurotransmission in Parkinson's disease

Pretreatment of rats, with the iron chelator VK-28, which is a relatively potent inhibitor of membrane lipid peroxidation and penetrates the brain, protected against 6-OHDA induced lesion of striatal dopamine neurons (Ben Shachar et al., 2004) similar to results obtained using desferal (Ben Shachar et al., 1991; Youdim et al., 2004c). This was confirmed by prevention of the reduction in striatal dopamine, DOPAC and HVA and the reduction in increased dopamine turnover normally seen with 6-OHDA. VK-28-induced protection is observed whether the chelator is given IVC or IP. Its neuroprotective activity is relatively more potent as compared to some other radical scavenging agents, such as vitamin E (Acuna-Castroviejo et al., 1997; Cadet et al., 1989; Ferger et al., 1998; Moussaoui et al., 2000; Perry et al., 1985; Roghani and Behzadi,

2001) used in 6-OHDA or the MPTP animal models. However, desferal's major limitation as a neuroprotective drug is its inability to cross the BBB. It is well established that intranigral or intraventricular 6-OHDA initiates an increase of total iron in the substantia nigra and striatum, at the sites of neurodegeneration, both in monkeys, rats and mice (Hall et al., 1992; Lin et al., 1997; Lin and Lin, 1997; Oestreicher et al., 1994). The process by which 6-OHDA or MPTP initiates iron accumulation in substantia nigra pars compacta is not fully known. It may depend on their abilities to release iron from ferritin, as well as to down regulate transferrin receptors and up regulate divalent metal transporter at the cell surface membrane, which can be prevented by iron chelators such as desferal (Monteiro and Winterbourn, 1989; Double et al., 1998; Linert et al., 1996; Lode et al., 1990; Mashetal., 1991; Pezzellaetal., 1997). These neurotoxin also inhibit mitochondrial complex I activity (Glinka and Youdim, 1965; Glinka et al., 1996 ) which can lead to oxida-tive stress dependent release of iron. Similar features have also been reported in the MPTP induced neurotoxicity in mice. The exact mechanism by which VK-28 produced neuroprotection is unclear, but we assume that similarly to desferal it chelates the iron and prevents complex I inhibition (Glinka et al., 1996).

Neither desferal or VK-28 have appreciable MAO inhibitory activities either in vitro or in vivo. M30 is an iron chelator, with equivalent potency to that of Vk-28 desferal (Zheng et al., 2005a, b). Similar to VK-28 it has radical scavenging activity and iron-induced membrane lipid peroxidation inhibitory potencies close to those of desferal (Zheng et al., 2005a, b). This is an advantage, since radical scavengers (Perry et al., 1985) such as vitamin E (Cadet et al., 1985), melatonin (Acuna-castroviejo et al., 1977), and the green tea polyphenols EGCG wich is an anti oxi-dant as well as a potent iron chelator (Mandel et al., 2005) have neuroprotective activity against MPTP and 6-OHDA neurotoxicity in vivo.

The M30 series of drugs were thus developed for two purposes. On the one hand, it was designed to prevent the ability of iron to induce oxidative stress, as a consequence of reactive hydroxyl radical generation via its interaction with hydrogen peroxide (Fenton Reaction). Secondly, M30 was designed to inhibit the formation of reactive hydroxyl radical from hydrogen peroxide generated by MAO and potentiate the pharmacological action of accumulated dopamine formed from L-dopa (L-dihydroxyphenylalanine).

MAO is considered one of the major enzymes that generate hydrogen peroxide which is also generated by several other oxidative reactions such as xanthine oxidase or by conversion of superoxide generated. If not adequately removed by brain glutathione per-oxidase, it can accumulate and interact with labile (ionic) iron. In PD substantia nigra (SN) GSH (reduced glutathione), the rate limiting co-factor of glutathione peroxidase diminishes significantly with the progression of the disease (Riederer et al., 1989; Sian et al., 1994). This together with accumulation of iron in SN would make dopamine neurons vulnerable to oxidative stress, unless iron is removed and MAO inhibited, thus preventing Fenton Reaction.

Besides its potent iron chelation and prevention of membrane lipid peroxidation, M30 is a potent inhibitor of MAO-A and B in all brain regions examined, with a slight preference for MAO-B (Gal et al., 2005). However, it is a poor inhibitor of the liver and small intestine MAO-A and B. This is a highly important pharmacological advantage of the drug, since irreversible inhibition of MAO-A which is prominent in these tissues is associated with the ''cheese reaction'' (potentiation of tyramine-induced cardiovascular activity), as has been observed with tranylcypromine, iproniazid and clorgyline. However, it is expected that M30 would not show such property. This is borne by the observation that our multifunctional cholinesterase-brain selective MAO-AB inhibitor, ladostigil (Weinstock et al., 2000) exhibits similar tissue MAO inhibitory properties and shows highly significant limited potentiation of tyramine-induced cardiovascular effect (Weinstock et al., 2002). The mechanism underlying the preference of M30 for the brain enzyme inhibition it not known. It is possible that in the brain, the inhibitor is metabolizm to active metabolite(s) that accumulate and are retained by the brain. The other possibility is that this drug inhibits its metabolized by a brain specific cytochrome P-450, which is absent in the liver and small intestine.

MAO-A and B enzyme inhibitory activity of M30 results in increased brain levels of dopamine, serotonin and noradrenaline. Thus, it is likely to have not only antiParkinson activity but also antidepressant property, similar to other non-selective MAO-AB (tra-nylcypromine) and selective MAO-A inhibitors (moclobemide) (see Youdim and Weinstock, 2004 for review). Similar to non selective MAO inhibitors and selective MAO-B inhibitors such as selegiline, rasagiline, lazabe-mide and milacemide (Foley et al., 2000), M30 prevents MPTP induced nigrostriatal dopaminergic neurotoxicity and dopamine depletion in mice, by protecting against the loss of dopamine neurons, by the presence of normal tyrosine hydroxylase activity. In contrast to the selective MAO-B or MAO-A inhibitors which do not increase brain levels of striatal dopamine (see Green et al., 1977; Lamensdorf et al., 1996; Finberg and Youdim, 2002), M30 caused significant increase in striatal DA, as well as 5-HT and NA levels, when given acutely either IP or PO. Thus, only when both enzyme forms are inhibited does brain dopamine increase and its metabolites DOPAC and HVA decrease (Green et al., 1977), as has been observed with M30. This is not unexpected since O'Carroll et al. (1983) showed that dopamine is equally well metabolized by both forms of the striatal human brain enzymes. Thus, when one enzyme form is inhibited, the other can continue to metabolize it (Green et al., 1977). Thus we have advocated on several occasions that an MAO inhibitor which inhibits both forms of brain MAO, and does not potentiate the cardiovascular action of tyramine, may have a superior dopamine neurotransmission po-tentiation and antiParkinson activity as compared to the selective MAO-A or -B inhibitors (Youdim and Weinstock, 2004). Chronic M30 treatment does not cause an increase in striatal dopamine. However, it significantly reduces DOPAC and HVA. Resulting in increased do-pamine turnover as reflected in DOPAC plus HVA/DA, and indicates increased DA release, as has been reported previously with other MAO inhibitors (Lamensdorf et al., 1996).

Conclusion

Free (chelatable) iron, more than any other transitional metal, plays a pivotal role in the processes of oxidative stress, inflammatory processes and cell death in many non neuronal and neuronal diseases. This is due to its cell abundance in brain regions (substantia nigra, globus pallidus, dentate gyrus, thalamus) associated with neuronal degeneration in neuro-degenerative diseases, profound redox state and decompartmentation from ferritin, which can result in oxidative stress, induce cell death as a consequence of reactive hydroxyl radical generation (Youdim and Riederer,

2004; Zecca et al., 2004) and its ability to release the excitotoxin glutamate (McGahan et al., 2005). The present study shows that the iron chelator M30 has potent iron chelating, radical scavenging and brain selective MAO-AB inhibitory activity (Fig. 2). In neuronal cell culture it has neuroprotective and neuro-rescue activity by regulating the anti apoptotic Bcl-family proteins and PKC activation similar to what has been established for rasagiline (Youdim, 2003; Avramowich et al., 2005). In vivo it induces neuroprotection against MPTP neurotoxicity and prevents the fall in striatal dopamine without affecting serotonin or noradrenaline as a consequence of its MAO inhibitory and iron chelating properties. The fact that it does this with IP treatment shows it crosses the blood brain barrier. M30 treatment increases the basal levels of the neurotrans-mitters dopamine, serotonin and noradrena-line in the absence and presence of MPTP indicating that it does not interfere with the iron dependent enzymes tyrosine hydroxy-lase and tryptophan hydroxylase activity. Thus, the multifunctional M30 and its other derivatives could be novel drug for the treatment of Parkinson's disease with and without depressive illness for which they are being developed.

Acknowledgements

The support of the ''Friedman Parkinson Research Found'' (Technion). National Parkinson Foundation (Miami, USA), Stein Foundation (Philadelphia, USA), Michael J. Fox Foundation (New York, USA) and The Weizmann Institute of Science (Rehovot, Israel) is gratefully acknowledged.

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Author's address: Prof. M. B. H. Youdim, Technion-Faculty of Medicine, Eve Topf and National Parkinson Foundation, Neurodegenerative Diseases Centers, Bat Galim, Haifa, Israel, e-mail: [email protected]

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