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Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro.

Abstract
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.
AuthorsOrit Bar-Am, Tamar Amit, Moussa B H Youdim
JournalJournal of neurochemistry (J Neurochem) Vol. 103 Issue 2 Pg. 500-8 (Oct 2007) ISSN: 0022-3042 [Print] England
PMID17635668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate
  • Indans
  • Neuroprotective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Sympatholytics
  • Tetrazolium Salts
  • Thiazoles
  • bcl-X Protein
  • rasagiline
  • Oxidopamine
  • Protein Kinase C
  • thiazolyl blue
Topics
  • Animals
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Line
  • Cell Survival (drug effects)
  • Humans
  • Indans (antagonists & inhibitors, metabolism, pharmacokinetics, pharmacology)
  • Neurons (drug effects)
  • Neuroprotective Agents (antagonists & inhibitors, pharmacokinetics, pharmacology)
  • Oxidopamine (toxicity)
  • PC12 Cells
  • Protein Kinase C (antagonists & inhibitors, physiology)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Rats
  • Sympatholytics (toxicity)
  • Tetrazolium Salts
  • Thiazoles
  • bcl-X Protein (metabolism)

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