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Journal of Molecular Neuroscience

, Volume 37, Issue 2, pp 135–145 | Cite as

The Novel Cholinesterase–Monoamine Oxidase Inhibitor and Antioxidant, Ladostigil, Confers Neuroprotection in Neuroblastoma Cells and Aged Rats

  • Orit Bar-Am
  • Orly Weinreb
  • Tamar Amit
  • Moussa B. H. YoudimEmail author
Article

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 μM) 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 (H2O2). In addition, ladostigil significantly upregulated mRNA levels of several antioxidant enzymes (catalase, NAD(P)H quinone oxidoreductase 1 and peroxiredoxin 1) in both H2O2-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.

Keywords

Alzheimer’s disease Ladostigil Oxidative stress Neuroprotection Antioxidant enzymes 

Abbreviations

beta amyloid

AChEI

acetyl cholinesterase inhibitor

AD

Alzheimer’s disease

APP

amyloid precursor protein

BDNF

brain-derived neurotrophic factor

BuChE

butyryl cholinesterase

ChE

cholinesterase

DEPC

diethylpyrocarbonate

DMEM

Dulbecco’s modified Eagle’s medium

FS

full serum

GDNF

glial-derived neurotrophic factor

G6PD

glucose-6-phosphate dehydrogenase

GPx

glutathione peroxidase

GSH-S

glutathione synthetase

GSHPX-P

glutathione peroxidase precursor H2O2, hydrogen peroxide

LB

Lewy body

MAO

monoamine oxidase

MAPK

mitogen-activated protein kinase

MTT

3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium

NO

peroxinitrite donor

NQ01

NAD(P)H quinone oxidoreductase 1

NMDA

N-methyl-d-aspartate

O2

superoxide anion radical

OS

oxidative stress

PD

Parkinson’s disease

PKC

protein kinase C

Prx 1

peroxiredoxin 1

ROS

reactive oxygen species

RT

reverse transcription

SIN-1

morpholinosydnonimine

SDS-PAGE

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

SOD

superoxide dismutase

TDPX1

thioredoxin peroxidase 1

Notes

Acknowledgement

The authors are grateful to Teva Pharmaceutical Co. (Netanya, Israel) and National Parkinson Foundation (Miami, FL, USA) and Stein Foundation and Friedman Foundations (Philadelphia, PA, USA) for their support of this work and to Smoler Proteomic Center, Department of Biology, Technion-Israel Institute of Technology for technical assistance.

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Copyright information

© Humana Press 2008

Authors and Affiliations

  • Orit Bar-Am
    • 1
  • Orly Weinreb
    • 1
  • Tamar Amit
    • 1
  • Moussa B. H. Youdim
    • 1
    • 2
    Email author
  1. 1.Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Faculty of MedicineTechnionHaifaIsrael
  2. 2.Department of Pharmacology, Faculty of MedicineTechnionHaifaIsrael

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