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The novel cholinesterase-monoamine oxidase inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats.

Abstract
The current therapeutic advance in which future drugs are designed to possess varied pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326; (N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase (MAO)-A and MAO-B and cholinesterase (ChE) inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy body disease. In the present study, we demonstrate that ladostigil (10(-6)-10 muM) dose-dependently increased cell viability, associated with increased activity of catalase and glutathione reductase and decrease of intracellular reactive oxygen species production in a cytotoxic model of human SH-SY5Y neuroblastoma cells exposed to hydrogen peroxide (H(2)O(2)). In addition, ladostigil significantly upregulated mRNA levels of several antioxidant enzymes (catalase, NAD(P)H quinone oxidoreductase 1 and peroxiredoxin 1) in both H(2)O(2)-treated SH-SY5Y cells, as well as in the high-density human SK-N-SH neuroblastoma cultured apoptotic models. In vivo chronic treatment with ladostigil (1 mg/kg per os per day for 30 days) markedly upregulated mRNA expression levels of various enzymes involved in metabolism and oxidation processes in aged rat hippocampus. In addition to its unique combination of ChE and MAO enzyme inhibition, these results indicate that ladostigil displays neuroprotective activity against oxidative stress-induced cell apoptosis, which might be valuable for aging and age-associated neurodegenerative diseases.
AuthorsOrit Bar-Am, Orly Weinreb, Tamar Amit, Moussa B H Youdim
JournalJournal of molecular neuroscience : MN (J Mol Neurosci) Vol. 37 Issue 2 Pg. 135-45 (Feb 2009) ISSN: 0895-8696 [Print] United States
PMID18751929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate
  • Antioxidants
  • Cholinesterase Inhibitors
  • Indans
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Oxidants
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • PRDX1 protein, human
  • Peroxiredoxins
  • Catalase
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
Topics
  • Aging
  • Animals
  • Antioxidants (chemistry, pharmacology)
  • Catalase (genetics)
  • Cell Count
  • Cell Line, Tumor
  • Cholinesterase Inhibitors (chemistry, pharmacology)
  • Gene Expression (drug effects)
  • Humans
  • Hydrogen Peroxide (toxicity)
  • Indans (chemistry, pharmacology)
  • Male
  • Monoamine Oxidase Inhibitors (chemistry, pharmacology)
  • NAD(P)H Dehydrogenase (Quinone) (genetics)
  • Neuroblastoma
  • Neurons (cytology, drug effects, metabolism)
  • Neuroprotective Agents (chemistry, pharmacology)
  • Oxidants (toxicity)
  • Peroxiredoxins (genetics)
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species (metabolism)

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