Abstract
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 (I1 & I2) are potential targets for TVP1022 (IC50 = 9.5E-08 M and IC50 = 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 I1 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 I1imidazoline receptor in mediating the cardioprotective activity of the drug. Our findings suggest that the I1imidazoline receptor represents a novel site of action for the cyto/cardio-protective efficacy of TVP1022.
Highlights
Much of the morbidity and mortality resulting from cardiovascular diseases is attributable to acute ischemic events leading to myocardial infarction and death of cardiac myocytes [1,2]
Our studies have previously shown that TVP1022, the Senantiomer of rasagiline (AzilectH) (N-propargyl-1R-aminoindan) features cyto/cardio-protective efficacy in a variety of experimental models
Using specific receptor binding and enzyme assays, the present findings demonstrated that I1 andI2 imidazoline binding sites are potential targets for TVP1022 (IC50 = 9.5E-08 M and IC50 = 1.4E-07 M, respectively)
Summary
Much of the morbidity and mortality resulting from cardiovascular diseases is attributable to acute ischemic events leading to myocardial infarction and death of cardiac myocytes [1,2]. We have reported previously that the compound TVP1022, which is the S-enantiomer of rasagiline (AzilectH) (N-propargyl-1R-aminoindan; a novel FDA-approved anti-Parkinsonian drug) possesses cytoprotective efficacy in a variety of cardiac and neuronal experimental models [5,6,7,8,9]. We have demonstrated that TVP1022 is ,1000 times less potent than rasagiline as a monoamine oxidase-B inhibitor [9,10], it exerts a prominent effective neuroprotective and antiapoptotic activities in neuronal cell cultures in response to various neurotoxins, and in in vivo model of head injury [5,8,9]. Studies on structure-activity relationship revealed that the neuroprotective effect of TVP1022 is associated mainly with its propargyl moiety, and is ascribed, at least partly, to the stabilization of mitochondrial membrane potential, induction of Bcl-2 and activation of p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways [7,9,10,11]
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