Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro.
The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-(R)-aminoindan. In the current study, the neuroprotective properties of 1-(R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1-1 mumol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindan-induced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCepsilon. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging.
Bar-Am
Orit
O
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.
Amit
Tamar
T
Youdim
Moussa B H
MB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013565:Sympatholytics / Q000633:toxicity; D013778:Tetrazolium Salts; D013844:Thiazoles; D051020:bcl-X Protein / Q000378:metabolism
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D007189:Indans; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013565:Sympatholytics; D013778:Tetrazolium Salts; D013844:Thiazoles; D051020:bcl-X Protein; C031967:rasagiline; D016627:Oxidopamine; D011493:Protein Kinase C; C022616:thiazolyl blue