Neuroprotective effect of rasagiline in a rodent model of Parkinson's disease

Abstract

Sprague–Dawley rats received a unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum and were treated daily for 6 weeks with increasing doses of monoamine oxidase type B inhibitor rasagiline [R(+)-N-propargyl-1-aminoindane] or saline (controls). Both doses of rasagiline markedly increased the survival of dopaminergic neurons in the lesioned substantia nigra, compared to controls (+97% and +119%, respectively). Treatment with the lower dose of rasagiline also abolished the motor stereotypies associated with nigrostriatal lesion. Our study supports the neuroprotective potential of chronic rasagiline administration in an experimental model of Parkinson's disease (PD).

Introduction

Various conditions, including mitochondrial defects, oxidative stress, and aberrant protein aggregation, may contribute to disrupt the physiological dynamics of apoptosis within the substantia nigra pars compacta (SNc), thus triggering the degenerative process underlying Parkinson's disease (PD) (Sherer et al., 2001). Monoamine oxidase type B (MAO-B) inhibitors of the propargylamine family have been extensively investigated for their potential neuroprotective properties (Tatton et al., 2003). The prototype of this class of compounds, selegiline, has shown antioxidant and neuroprotective effects in experimental studies, although the neuroprotective activity in PD patients has remained controversial (Tatton et al., 2003). Considerable attention has been recently attracted by rasagiline [R(+)-N-propargyl-1-aminoindane], the most potent propargylamine, which, although structurally related to selegiline, is different in that it is not metabolized to amphetamine and/or metamphetamine Finberg et al., 1999, Youdim et al., 2001a. Phase III clinical studies have already reported significant efficacy of rasagiline for PD treatment, either as adjunct therapy to l-Dopa (Rabey et al., 2000) or as monotherapy in early PD (Parkinson Study Group, 2002).

Numerous studies have reported that rasagiline can prevent cell death induced by various stimuli. In vitro, the drug has shown anti-apoptotic activity in partially–neuronally differentiated rat PC-12 cells treated with pro-apoptotic agents (Maruyama et al., 2001); rasagiline also increases the expression of anti-apoptotic and prosurvival proteins Akao et al., 2002b, Youdim et al., 2003, and reduces markers of altered mitochondrial activity Akao et al., 2002b, Naoi et al., 2002). Recent studies have shown that treatment with rasagiline protects against serum, and nerve growth factor withdrawal induced death in PC-12 cells (Am et al., 2004), and increases the expression of glial cell line-derived neurotrophic factor in human dopamine-derived neuroblastoma cells (SH-SY5Y) through the activation of the nuclear transcription factor NF-κB (Maruyama et al., 2004). Rasagiline has also shown potent activity against 6-hydroxydopamine (6-OHDA) toxicity, both in PC-12 and SH-SY5Y cells (Maruyama et al., 2000). Similar effects have been observed for the S-isomer of rasagiline, which is 1000 times less active on MAO (Youdim et al., 2001a), thus suggesting that MAO-B inhibition may not be central in the protective activity of the drug, which is likely related to intrinsic anti-apoptotic properties Abu-Raya et al., 2002, Akao et al., 2002b, Youdim et al., 2001b, Youdim et al., 2003. Neuroprotection by rasagiline has been substantially confirmed in vivo with several animal models Huang et al., 1999, Speiser et al., 1999; however, relatively few data are available on the ability of rasagiline to block SNc degeneration in animal models of PD, particularly after chronic administration. In fact, rasagiline and—previously—its racemate, AGN 1135, have proven able to prevent the nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in monkeys, when given before the toxin Heikkila et al., 1985, Kupsch et al., 2001. In this study, we explored the neuroprotective potential of chronic rasagiline administration in a rodent model of PD based on the intrastriatal injection of 6-OHDA, a procedure that causes a slowly evolving lesion of dopaminergic cell bodies in the SNc and is therefore recommended for neuroprotection studies (Deumens et al., 2002).