The importance of propargylamine moiety in the anti‐ Parkinson drug rasagiline and its derivatives for MAPK‐ dependent amyloid precursor protein processing

Abstract

Rasagiline [N-propargyl-(1R)-aminoindan] a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor exerts neuroprotective and antiapoptotic effects against a variety of insults in cell cultures and in vivo and has finished its phase III clinical trials for Parkinson's disease. In the present study, we show that rasagiline (1 and 10 microM) significantly protected rat PC12 cells against beta-amyloid (Abeta1-42) toxicity. In addition, rasagiline significantly increased (approximately threefold) the secretion of the nonamyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) from SH-SY5Y neuroblastoma and PC12 cells. The increase of sAPPalpha was dose-dependent and was blocked by the hydroxamic acid-based metalloprotease inhibitor Ro31-9790 (100 microM), suggesting that the effect is mediated via alpha-secretase activity. Rasagiline-induced sAPPalpha release was significantly reduced by the inhibitors of protein kinase C (PKC), GF109203X, and ERK mitogen-activated protein kinase (MAPK) PD98059. Moreover, rasagiline dose dependently (0.1-10 microM) increased the phosphorylation of p44 and p42 MAPK, which was abolished by PD98059 (30 microM) and GF109203X (2.5 microM). By comparing the actions of rasagiline with those of its S-isomer TVP1022, which is not an MAO inhibitor, we have been able to demonstrate that MAO-B inhibition is not a prerequisite for either sAPPalpha-induced release or ERK phosphorylation. In addition, structure-activity relationship among rasagiline-related compounds suggests the crucial role of the propargyl moiety in these molecules, because propargylamine itself significantly induced the secretion of sAPPalpha and increased MAPK phosphorylation with similar potency to that of rasagiline and its derivatives.

Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway

“…The activation of proÀsurvival PKC isoforms associated with BclÀ2 family members, the MAPK pathway and induction of neuroptrophic factors by rasagiline and its propargyl moiety [18,44,45] are novel mechanisms of action, which are currently considered in developing new neuroprotective drugs that address multiple central nervous system etiological targets associated with neuropsychiatric disorders [46]. The recent studies demonstrating a neuronal restoration of synaptic transmission in brains of PD animal model, suggest a possible diseaseÀmodifying activity of rasagiline [5].…”

Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil

“…Accordingly we have recently shown that PKC and MAPK pathways may be involved in the enhancement of sAPPα release by ladostigil (Yogev-Falach et al, 2002). However, the effect dose not appear to result from its ChE inhibitiory activity, since rasagiline and N-propargylamine, which do not inhibit ChE, were also able to induce PKC and ERK activation and promote sAPPα release (Yogev-Falach et al, 2003).…”

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

“…18,20 Similarly, GF109203X, and the extracellular signal-regulated kinase (ERK)1/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. 22 The importance of PKC pathway in rasagiline-and propargylamine-induced neuroprotective activity is supported also by previous data demonstrating that these compounds 20,22 induced the release of the neuroprotective-neurotrophic nonamyloidogenic soluble amyloid precursor protein ␣ (sAPP␣) by MAPK-and PKC-dependent mechanisms in vitro. 18 -21 Current therapeutic approaches suggest that drugs acting at a single target may be insufficient for the treatment of multifactorial neurodegenerative diseases such as PD, Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), all characterized by the coexistence of multiple etiopathologies.…”

“…However, this neuroprotective effect of ladostigil does not appear to result from its ChE inhibition activity only, since rasagiline or propargylamine were also able to induce PKC and ERK activation and promote sAPP␣ release. 22 Several ChEIs, such as tacrine, 80 physostigmine, 81 metrifonate, 82 ganstigmine, 83 and donepezil 84 increased sAPP␣ release in cell culture. However, the observations that phenserine 78 and tacrine, at high concentration, 85 decreased sAPP␣ release suggests that the regulation of APP processing by ChEIs is not simply associated to AChE inhibition.…”