The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in 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.