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

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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.

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Abbreviations

Aβ:

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

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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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  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 Medicine, Technion, Haifa, 31096, Israel

    Orit Bar-Am, Orly Weinreb, Tamar Amit & Moussa B. H. Youdim

  2. Department of Pharmacology, Faculty of Medicine, Technion, P.O. Box 9697, 31096, Haifa, Israel

    Moussa B. H. Youdim

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  1. Orit Bar-Am
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  2. Orly Weinreb
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  4. Moussa B. H. Youdim
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Correspondence to Moussa B. H. Youdim.

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Orit Bar-Am, Orly Weinreb, and Tamar Amit share equal recognition.

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Bar-Am, O., Weinreb, O., Amit, T. et al. The Novel Cholinesterase–Monoamine Oxidase Inhibitor and Antioxidant, Ladostigil, Confers Neuroprotection in Neuroblastoma Cells and Aged Rats. J Mol Neurosci 37, 135–145 (2009). https://doi.org/10.1007/s12031-008-9139-6

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