Rasagiline: A novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity

Abstract

Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. Rasagiline is effective as monotherapy or adjunct to l-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline. This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action.

Introduction

The knowledge that dopamine (DA) is oxidatively deaminated equally by monoamine oxidase (MAO) types A and B (Collins et al., 1970), the dominance of MAO-B (80%), as compared to MAO-A in the extrapyramidal regions of human brain (Collins et al., 1970, O’Carroll et al., 1983, Squires, 1972) and the absence of “cheese reaction” in whole animal and isolated tissue preparations by the selective irreversible MAO-B inhibitor, l-deprenyl (selegiline) (Sandler et al., 1978), led to introduce the irreversible selective MAO-B inhibitor, selegiline as an adjunct to l-Dopa therapy of Parkinson's disease (PD) (Birkmayer et al., 1977, Birkmayer et al., 1975, Lees et al., 1977). The drug has been useful as an anti-Parkinson drug, both in monotherapy and as adjunct to l-Dopa therapy [the DATATOP (deprenyl and tocopherol antioxidative therapy of Parkinsonism)] (Parkinson Study Group, 1993, Parkinson Study Group, 1996, Parkinson Study Group, 1998, Parkinson Study Group, 1989), and has a l-Dopa sparing action (Birkmayer et al., 1977, Riederer et al., 1978). Selegiline irreversibly inhibits MAO-B by binding, mole per mole, covalently to the N-5 position of the isoalloxazine moiety of flavin adenine dinucleotide (FAD), the cofactor of MAO-B (Maycock et al., 1976, Riederer et al., 1982, Youdim, 1978). Selegiline is a propargylamine-derivative of l-amphetamine, and is metabolized in vivo to its major toxic metabolites l-amphetamine and l-methamphetamine (Reynolds et al., 1978) (Fig. 1). Thus, in pharmacological preparations and in vivo it possesses amphetamine-like sympathomimetic actions, which may result in increased blood pressure and heart rate, although in clinical practice it may not have a significant role compared to all other anti-Parkinsonian drugs (Finberg et al., 1981a, Simpson, 1978).

Based on these studies with selegiline, a new highly potent irreversible selective inhibitor of MAO-B, rasagiline [N-propargyl-1-(R)-aminoindan; TVP1012; Azilect] (Fig. 1), was identified and developed as an anti-Parkinsonian drug (Finberg et al., 1996, Finberg et al., 1999, Kalir et al., 1981, Sabbagh and Youdim, 1978, Sterling et al., 1998, Youdim and Bakhle, 2006, Youdim et al., 2001a). Rasagiline is the R-isomer of the selective MAO-B inhibitor, AGN 1135 (Kalir et al., 1981, Sabbagh and Youdim, 1978). In preclinical studies, rasagiline was shown to possess neuroprotective activity (Heikkila et al., 1985, Maruyama et al., 2001a, Tatton et al., 2002, Weinreb et al., 2004). More prominently, rasagiline induced an in vivo neurorestorative activity in the substantia nigra pars compacta (SNpC) neurons, when given post-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lactacystin (proteasome inhibitor) (Sagi et al., 2007, Zhu et al., 2008). This property was shown to be associated with activation of tyrosine kinase (TK) receptor and stimulation of various cell signaling transduction pathways (Sagi et al., 2007). An additional neuroprotective effect, shared by rasagiline and other propargyl derivative compounds is related to their ability to regulate the non-amyloidogenic processing of the Alzheimer's disease (AD) amyloid precursor protein (APP) (Bar-Am et al., 2004b, Yogev-Falach et al., 2002, Yogev-Falach et al., 2003). Thus, rasagiline may induce neuroprotective, neurorescue and long-term potentiating effects. Indeed, recent Phase III delayed-start clinical study in Parkinsonian subjects, ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) indicated that rasagiline might be the first drug with the benefits of slowing the disease progression (Olanow et al., 2008, Olanow et al., 2009).

At its selective MAO-B inhibitory dosage, rasagiline does not produce the “cheese reaction”, as was shown in isolated tissue preparations or in vivo in rats and cats (Finberg et al., 1981a, Finberg and Youdim, 1985). Unlike selegiline, rasagiline is primarily metabolized by hepatic cytochrome P-450 isoenzyme 1A2 (CYP1A2)-mediated N-dealkylation to form the non-toxic compound 1-(R)-aminoindan (Fig. 1) (Chen and Swope, 2005, Chen et al., 2007). A kinetic and crystallographic analysis revealed that 1-(R)-aminoindan is not a substrate for MAO oxidation, but conversely, a weak reversible inhibitor (Sterling et al., 1998, Binda et al., 2005). Recent studies indicated the potential neuroprotective effect of 1-(R)-aminoindan, suggesting that it may contribute to the overall neuroprotective and anti-apoptotic effects of rasagiline (Bar-Am et al., 2004a, Bar-Am et al., 2007, Bar-Am et al., 2010). The current review presents findings-based studies of the pharmacology of rasagiline in PD and discusses its applicable functional mechanisms of action.