title: I1 imidazoline receptor: novel potential cytoprotective target of TVP1022, the S-enantiomer of rasagiline.
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 (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.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Yaron D
authors.initials: YD
authors.lastname: Barac
authors.forename: Orit
authors.initials: O
authors.lastname: Bar-Am
authors.forename: Esti
authors.initials: E
authors.lastname: Liani
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.forename: Luba
authors.initials: L
authors.lastname: Frolov
authors.forename: Elena
authors.initials: E
authors.lastname: Ovcharenko
authors.forename: Itzchak
authors.initials: I
authors.lastname: Angel
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Ofer
authors.initials: O
authors.lastname: Binah
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001572:Benzofurans; D002316:Cardiotonic Agents; D007093:Imidazoles; D054755:Imidazoline Receptors; D007189:Indans; C410887:imidazoline I1 receptors; C031967:rasagiline; D019950:Mitogen-Activated Protein Kinase 1; C062597:efaroxan