TVP1022, the S-enantiomer of
rasagiline (Azilect®) (N-propargyl-1R-aminoindan), exerts cyto/cardio-protective effects in a variety of experimental cardiac and neuronal models. Previous studies have demonstrated that the protective activity of
TVP1022 and other propargyl derivatives involve the activation of p42/44
mitogen-activated protein kinase (MAPK) signaling pathway. In the current study, we further investigated the molecular mechanism of action and signaling pathways of
TVP1022 which may account for the cyto/cardio-protective efficacy of the
drug. Using specific receptor binding and
enzyme assays, we demonstrated that the
imidazoline 1 and 2 binding sites (I(1) & I(2)) are potential targets for
TVP1022 (IC(50) =9.5E-08 M and IC(50) =1.4E-07 M, respectively). Western blotting analysis showed that
TVP1022 (1-20 µM) dose-dependently increased the immunoreactivity of phosphorylated p42 and
p44 MAPK in rat
pheochromocytoma PC12 cells and in neonatal rat ventricular myocytes (NRVM). This effect of
TVP1022 was significantly attenuated by
efaroxan, a selective I(1)
imidazoline receptor antagonist. In addition, the cytoprotective effect of
TVP1022 demonstrated in NRVM against serum deprivation-induced toxicity was markedly inhibited by
efaroxan, thus suggesting the importance of I(1)
imidazoline receptor in mediating the cardioprotective activity of the
drug. Our findings suggest that the I(1)
imidazoline receptor represents a novel site of action for the cyto/cardio-protective efficacy of
TVP1022.