Involvement of multiple survival signal transduction pathways in the neuroprotective neurorescue and APP processing activity of rasagiline and its propargyl moiety

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O. Weinreb, T. Amit, O. Bar-Am, Y. Sagi, S. Mandel, and M. B. H. Youdim

Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel

Summary. Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCa, PKCe and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neuro-trophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCg mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propar-gylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahy-dropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.

Introduction

Rasagiline (N-propargyl-1-(R)-aminoindan), a potent selective irreversible inhibitor of monoamine oxidase (MAO)-B, is a novel anti-Parkinsonian drug, which may have disease modifying properties. In light of recently reported benefits in patients with early illness, rasagiline is a promising new treatment for Parkinson's disease (PD) (Parkinson Study Group, 2005). Recent multi-center doubleblind mono-therapy with rasagiline by the Parkinson Study Group (Parkinson Study Group, 2004) and as adjunct therapy to L-DOPA (Rabey et al., 2000), has shown that rasagiline confers significant symptomatic improvement and suggested possible alterations in disease progression at doses of 1 and 2 mg (Chen and Swope, 2005). Rasagiline has been shown to have a broad neuroprotec-tive activity against a variety of neurotoxins in neuronal cell cultures and in animal models.

Rasagiline

Rasagiline

Propargylamine

Fig. 1. The chemical structures of the anti-Parkinson's drug/MAO-B inhibitor, rasagiline and its propargyl moiety, propargylamine

This includes attenuation of cell death in partially differentiated rat pheochromocytoma (PC12) cells deprived of serum and nerve growth factor (NGF) (Maruyama et al., 2000b) and neuroprotection against the endogenous neurotoxin N-methyl-(R)-salsolinol (N-M-(R)-Sal) (Akao et al., 2002; Maruyama et al., 2001a, b), 6-hydroxydopamine (6-OHDA) (Maruyama et al., 2000a), SIN-1 (a peroxy-nitrite donor) (Maruyama et al., 2002a, b) and glutamate toxicity (Finberg et al., 1999) in neuronal cells. In vivo studies have described the protective effect of rasagiline in N-Methyl- 4 -phenyl-1, 2,3, 6 - tetrahydropyr-idine (MPTP) model in mice and monkeys, preventing its conversion to 1-methyl-4-phe-nylpyridinium (MPP+) (Heikkila et al., 1985), in focal ischemia model in rats (Speiser et al., 1999) and in neurotrauma model of head injury in mice (Huang et al., 1999). In addition, rasagiline suppresses the cell death cascade initiated by pro-apoptotic mitochondrial proteins, prevents decline in mitochondrial membrane potential (A^m), inhibits the apoptotic processes including activation of caspase3, nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and DNA fragmentation (Maruyama et al., 2002b; Youdim et al., 2003).

Our recent studies investigated new aspects of the pro-survival effects of rasagiline and its propargyl moiety, propargylamine (Fig. 1), in serum deprivation-neuroprotect-ive/neurorescue-models, using rat PC12 cells and human SH-SY5Y cells. The molecular mechanisms of the neuroprotective/neuro-rescue effects of rasagiline and propargyl-

amine on pro- and anti-apoptotic proteins, neurotrophic factors and amyloid precursor protein (APP) regulation are discussed in this review.

The mechanisms underlying neuroprotective activity of rasagiline and propargylamine

A major pathway implicated in neuronal cell survival is the intrinsic or mitochondrial signaling, triggered and mediated by the Bcl-2 family members that may either support cell survival (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1/ Bfl-1) or promote cell death (Bax, Bak, Bcl-Xs, Bad, Bid, Bik, Hrk, Bok) (Cory and Adams, 2002). The pro-apoptotic proteins of the Bcl-2 family members may trigger the opening of the mitochondrial mega-channel, or a specific channel in the outer mitochon-drial membrane, both of which promote the fall in mitochondrial membrane potential, leading to cytochrome c release (Bernardi et al., 2001; Kroemer and Reed, 2000). The competitive action of the pro-and anti-survival Bcl-2 family proteins regulates the activation of the caspases which dismantle the cell (Adams and Cory, 1998; Evan and Little-wood, 1998; Zamzami et al., 1998). Bcl-2 overexpression was shown to prevent cell death, probably by inhibiting Bax translocation and insertion into mitochondrial membrane, or via a direct interaction with the channels (Cheng et al., 2001). Rasagiline was recently shown to prevent the fall in mito-chondrial membrane potential (A^m) and the opening of mitochondrial voltage depen dent anion channel via the increase in Bcl-2 and Bcl-xL proteins (Maruyama et al., 2000a, 2002a). This is consistent with recent study (Weinreb et al., 2004) provided evidence that the neuroprotection effect of rasagiline is mediated by gene regulation of the Bcl-2-re-lated protein family. Neuroprotection experiments were done in serum-starved partially differentiated rat PC12 cells. Cell viability was markedly reduced by 24 h serum withdrawal. Both rasagiline and its propargyl moiety, propargylamine, significantly reduced cell death induced by serum deprivation. The finding that propargylamine (Weinreb et al., 2004) had similar effects with the same potency as rasagiline, enlightens the importance of the propargyl moiety for the neuroprotection activity of rasagiline.

These drugs also decreased the mRNA of the pro-apoptotic members, Bax and Bad and increased the mRNA of the cell survival members, Bcl-2, Bcl-w and Bcl-xL. Additionally, the involvement of protein kinase C (PKC) pathway in rasagiline-induced inactivation of the BH3-only pro-apoptotic Bcl-2 family member, Bad, was demonstrated (Weinreb et al., 2004). This was consistent with PKC-dependent promotion of cell survival via phosphorylation and inactivation of Badmediated cell death (Tan et al., 1999). Thus, PKCa is known to phosphorylate Bcl-2 in a site that increases its anti-apoptotic function (Ruvolo et al., 1998) and overexpression of PKCe results in increased expression of Bcl-2 (Gubina et al., 1998). Moreover, suppression of PKCa triggers apoptosis through down-regulation of Bcl-xL (Hsieh et al., 2003). The role for PKC activation in the neuroprotective mechanism of rasagiline and propargylamine, is supported by the results that both compounds can activate p-PKC levels and up-regulate essential PKC isoforms involved in cell survival pathways, PKCa and PKCe, in mice hippocampus (Bar-Am et al., 2004) and in starved PC12 cells (Weinreb et al., 2004). Rasagiline also down-regulated detrimental PKCg in serum-deprived PC12

cells (Weinreb et al., 2004). The inhibition of PKC activity has blocked the neuroprotec-tive action of rasagiline and its propargyl moiety compound in serum-deprived PC12 cells. The specific broad spectrum PKC inhibitor, GF109203X, which exhibits high affinity for the conventional PKCs (a, b, g), as well as the novel isoenzyme PKCe (Gekeler et al., 1996; Ku et al., 1997), markedly reversed rasagiline-suppressive effects on the protein expression of the pro-apoptotic regulator/cell death machinery, Bad, and on the cleavage and activation of pro-caspase-3 and poly (ADP-ribose) polymerase (PARP), in serum withdrawal-induced programmed cell death (Weinreb et al., 2004). Similarly, GF109203X, and the ERK1 /ERK2 inhibitor, PD98059, prevented rasagiline-activation/ phosphorylation of p42 and p44 mitogen-activated protein kinase (MAPK), thus indicating that rasagiline directly activates PKC-MAPK pathway (Yogev-Falach et al., 2003). The importance of PKC pathway in rasagiline-neuroprotective activity is supported also by previous data demonstrating that rasagiline (Yogev-Falach et al., 2003) induced the release of the neuroprotective-neurotrophic non-amyloidogenic soluble APP (sAPPa) by MAPK-and PKC-dependent mechanisms in vitro (Yogev-Falach et al., 2002).

Rasagiline has been shown to cause up-regulation of antioxidative proteins, such as superoxide dismutase (SOD) and glutathione (Youdim, 2003; Youdim and Weinstock, 2002). Nonetheless it is unlikely that the neu-roprotective effect of rasagiline is related to MAO-B inhibition, because PC12 cells contain only MAO type A (Youdim, 1991; Youdim et al., 2001). Moreover, the S-isomer of rasagiline, TVP1022, which is not an inhibitor of MAO-A or -B also protected serum-deprived PC12 cells from cell death, suggesting that the mode of action is independent of MAO inhibition. These results are consisting with previous reports providing clear evidence that the neuroprotection by rasagiline and its derivatives does not depend on inhibition of MAO-B (Youdim et al., 2003), but rather is associated with some intrinsic pharmacological action of the propargyl moiety in these compounds acting on the mitochondria cell survival proteins.

Additional neuroprotective mechanism of rasagiline involves the up-regulation of the expression levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), as demonstrated in neuronal cells (Maruyama et al., 2004; Weinreb et al., 2004). Indeed, both neurotrophic factors have been shown to induce neuroprotective and neurorescue activity in dopaminergic and cholinergic neurons, and promote survival of major neuronal types affected in Alzheimer Disease (AD) and PD (Murer et al., 2001; Wang et al., 2002). Recently, rasagiline was proved to increase the protein and mRNA levels of GDNF in neuroblastoma cells through activation of nuclear factor-kappaB (NF-kappaB) transcription factor (Maruyama et al., 2004). These results indicate that the induction of neuro-trophic factors by rasagiline might suppress apoptosis in neurodegenerative diseases and may support a possible disease-modifying activity of rasagiline (Blandini, 2005).

Neurorescue activity of rasagiline and propargylamine

The widespread hypothesis suggests that apoptosis is the predominant mode of neuronal death in neurodegenerative disorders, such as AD and PD. Since diagnosis of neurodegen-erative diseases is based on the appearance of clinical characteristics, patients have already suffered massive neuronal degeneration. Only 10% to 30% of normal neuronal population is surviving in the clinical stage of the disease. Therefore, there is a significant effort to develop drugs with neurorescue activity for therapy in the clinically diagnostic patients.

Consistent with the finding of the neuro-protective mechanism of rasagiline and pro-

pargylamine, recent study (Bar-Am et al., 2005) demonstrated that the neurorescue activity of these two drugs are also mediated by the Bcl-2 family proteins and the neuro-trophic factors GDNF and BDNF. In this study, using human SH-SY5Y neuroblastoma cells, a prolonged serum deprivation-neuro-rescue model was established, in which the cells were exposed to serum free media 3 days prior to the administration of rasagiline and propargylamine. In these extreme serum deprived-conditions, the severe loss of viability was due to apoptotic cell death, detected by a significant up-regulation of apoptotic-associated parameters, including cleaved caspase-3 and PARP and the early apoptosis-associated phosphorylated protein, H2A.X. The neurorescue effects of rasagiline and propargylamine (Bar-Am et al., 2005), was characterized by the reduction in the cleavage of caspase-3 and PARP, as well as in phosphorylated histone, H2A.X levels. The pro-survival effects of both drugs were mediated by the Bcl-2 family proteins, thus increasing both Bcl-2/Bax ratio of mRNA and protein levels and reducing the ''BH3-only'' proteins, Bad and Bim.

As another mechanism of neurorescue, propargylamine was found to up-regulate gene expression levels of GDNF and BDNF following long-term serum deprivation of SH-SY5Y cells (Bar-Am et al., 2005). These results indicate that the induction of neuro-trophic factors by propargyl-related derivatives and propargylamine and might suppress apoptosis in neurodegenerative diseases. Indeed, controlled clinical studies with rasagi-line suggested the possible disease modifying action of rasagiline in PD patients (Blandini, 2005). In recent study, chronic low doses of rasagiline administered to mice subsequently to MPTP, rescued dopaminergic neurons in the substantia nigra pars compacta (Sagi et al., 2005). Employing proteomic and genomic screening tools combined with a biology-based clustering method, we demonstrated that rasagiline induced a number of cell signaling mediators associated with the tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras, in parallel with a specific increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) proteins. Confirmatory immunohistochemical analysis indicated that this effect was associated with activation of the substrate of PI3K, Akt and phosphorylation/inactivation of glycogen synthase kinase-3b and Raf1. These results demonstrated the essentiality of the activation of Ras-PI3K-Akt survival pathway in rasagiline-mediated neurorescue effect.

Regulation of holo-APP levels and sAPPa release by rasagiline and propargylamine

In AD, increased expression and/or altered processing of APP causing an increase in generation of ß-amyloid peptides, may play a central role in the amyloidogenesis process (Bush, 2003), leading to the formation of the senile plaque (Mills and Reiner, 1999; Turner et al., 2003). A common mechanism leading to up-regulation of holo-APP expression and Aß formation is the shortage of energy

Fig. 2. Schematic overview demonstrating protein and gene targets involved in the neuroprotective activity of the anti-Parkinson drug rasagiline and propargylamine, with respect to their proposed modulating effect on signal transduction pathway, neurotrophic factors, and APP regulation in vitro and in vivo

Fig. 2. Schematic overview demonstrating protein and gene targets involved in the neuroprotective activity of the anti-Parkinson drug rasagiline and propargylamine, with respect to their proposed modulating effect on signal transduction pathway, neurotrophic factors, and APP regulation in vitro and in vivo supply, related oxidative stresses and apop-tosis. Indeed, rasagiline significantly protected rat PC12 cells against amyloid-beta peptide (Aß 1-42)-toxicity (Yogev-Falach et al., 2002). In addition, rasagiline and propargyl-amine both significantly down-regulated holo-APP protein levels in the neurorescue model, in human neuroblastoma SH-SY5Y cells (Bar-Am et al., 2005). Thus, this observation could be of a value in reducing Aß formation. In agreement, recent in vivo studies demonstrated that rasagiline and its anti-Alzheimer cholinesterase-brain selective MAO inhibitor derivative, ladostigil (Youdim et al., 2005) reduced the levels of cell-associated holo-APP in mice hippocampus (Bar-

Am et al., 2004). Structure-activity has clearly shown that a-secretase dependent processing of APP is associated with the propargyl moiety of rasagiline, since propargylamine itself has similar action, but not aminoindan, the metabolite of rasagiline (Bar-Am et al., 2004). The regulatory mechanism of these drugs on holo-APP expression is presumably post-transcriptional, since they suppress holo-APP protein levels without altering mRNA expression. Additionally, both rasagiline and propargylamine increased sAPPa levels in the medium of serum-deprived SH-SY5Y cells, via activation of PKC and MAPK pathway (Yogev-Falach et al., 2002, 2003).

Fig. 3. Proposed schematic model for the neurorescue effects of rasagiline and propargylamine involving regulation of the expression levels of anti/pro-apoptotic proteins and genes, neurotrophic factors and APP

processing

Fig. 3. Proposed schematic model for the neurorescue effects of rasagiline and propargylamine involving regulation of the expression levels of anti/pro-apoptotic proteins and genes, neurotrophic factors and APP

processing

Conclusions

Multiple signaling pathways have been identified (Figs. 2 and 3) that may be involved in the neuroprotective/neurorescue mechanism of action of rasagiline and propargylamine. The significant novel findings in these described studies is that although the propargylamine, the three carbon active moiety of rasagiline, which is an extremely poor inhibitor of MAO (IC50 >50 mM) (Zheng et al., 2005a), it has a similar potency of neuroprotective/ neurorescue and APP processing activity as the parent drug rasagiline. We have recently demonstrated (Zheng et al., 2005b) that introduction of the propargyl moiety into other drugs, such as iron chelators (e.g.VK-28) and radical scavengers, which we have developed for the treatment of neurodegenerative diseases (Youdim and Buccafusco, 2005; Zecca et al., 2004), render them multifunctional drugs targeting various central nervous system disorders. The molecular mechanism which is described in the present paper (Figs. 2 and 3) enlighten the crucial pharmacological activity of the propargyl moiety in rasagiline. Future research on structure-activity relationship of aminoindan, the second metabolite of rasagiline, will indicate its role in the mechanism of action of rasagiline and clarify the possible disease-modifying activity of the drugs, as suggested in clinical trials of early PD patients (Parkinson Study Group, 2005).

Acknowledgements

The support of Teva Pharmaceutical Co. (Netanya, Israel), National Parkinson Foundation (Miami, USA), Stein Foundation (Philadelphia, USA) and Rappaport Family Research Institute, Technion-Israel Institute of Technology and Golding Parkinson Research Fund (Technion, Haifa) are gratefully acknowledged.

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Author's address: Dr. O. Weinreb, Department of Pharmacology, Technion-Faculty of Medicine, P.O.B. 9697, 31096 Haifa, Israel, e-mail: [email protected] tx.technion.ac.il

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