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Apoptosis

, Volume 15, Issue 6, pp 738–751 | Cite as

Attenuation of NF-κB and activation of Nrf2 signaling by 1,2,4-triazine derivatives, protects neuron-like PC12 cells against apoptosis

  • Solaleh Khoramian Tusi
  • Niloufar Ansari
  • Mohsen Amini
  • Azim Dehghani Amirabad
  • Abbas Shafiee
  • Fariba KhodagholiEmail author
Original Paper

Abstract

Oxidative stress has been implicated in the etiology of neurodegenerative diseases and aging. Indeed, accumulation of reactive oxygen species, such as hydrogen peroxide, generated by inflammatory cells, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders of the central nervous system, such as Alzheimer’s disease. The present study indicates that H2O2-induced cell death can be inhibited in the presence of 1,2,4-triazine derivatives, as measured by MTT and caspase-3 activity. We further show that these compounds exert their protective effect by up-regulation of hemeoxygenase-1, glutamylcysteine synthetase, glutathione peroxidase and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), while they inhibit NF-κB and decrease lipid peroxidation. It shows that there is a potential cross talk between NF-κB and Nrf2, an important cytoprotective transcription factor in the presence of these compounds. Moreover, in order for drugs to be effective in the treatment of neurodegenerative diseases, they must be capable of penetrating the blood–brain barrier, whereas more than 98% of all potential central nervous system drugs don’t cross. Using a reliable model based on the artificial neural network indicated that these compounds satisfy this requirement.

Keywords

Alzheimer’s disease Artificial neural network NF-κB Nrf2 PC12 cells Triazine derivatives 

Abbreviations

Amyloid β

AD

Alzheimer’s disease

ANN

Artificial neural network

AREs

Antioxidant responsive elements

BBB

Blood–brain barrier

CAT

Catalase

CNS

Central nervous system

CSBP

Plasma protein binding ratio

ECL

Electrochemiluminescence

γ-GCS

γ-Glutamylcysteine synthetase

GPx-1

Glutathione peroxidase

GSH

Glutathione

HBA

Abraham’s hydrogen-bond acidity

HBB

Hydrogen-bond basicity

HO-1

Hemeoxygenase-1

H2O2

Hydrogen peroxide

Keap1

Kelch-like ECH-associated protein 1

MDA

Malondialdehyde

MTT

3-[4,5-dimethylthiazol-2-yl]-2,5-dephenyl tetrazolium bromide

NF-κB

Nuclear factor-κB

NGF

Nerve growth factor

NRB

Number of rotable bonds

Nrf2

Nuclear factor-erythroid 2 p45-related factor 2

P-gp (H)

High affinity p-gp substrate probability

PSA

Polar surface area

RMS

Root-mean-sequare

ROS

Reactive oxygen species

SOD

Superoxide dismutase

Notes

Acknowledgments

F. Khodagholi And M. Amini thank National Elite Fund, Iran, for the award of Young Scientist Research Fellowship. This work was supported partially by Shahid Beheshti University of Medical Sciences Research Funds and Tehran University of Medical Sciences Research Council. The authors thank Fatemeh Shaerzadeh for her excellent technical assistance.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Solaleh Khoramian Tusi
    • 1
  • Niloufar Ansari
    • 1
    • 2
  • Mohsen Amini
    • 2
  • Azim Dehghani Amirabad
    • 1
  • Abbas Shafiee
    • 3
  • Fariba Khodagholi
    • 1
    Email author
  1. 1.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Department of Medicinal Chemistry, Faculty of Pharmacy, and Drug Design & Development Research CenterTehran University of Medical SciencesTehranIran
  3. 3.Department of Medicinal Chemistry, Faculty of Pharmacy, and Pharmaceutical Sciences Research CenterTehran University of Medical SciencesTehranIran

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