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

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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.

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Abbreviations

Aβ:

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

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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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Authors and Affiliations

  1. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Solaleh Khoramian Tusi, Niloufar Ansari, Azim Dehghani Amirabad & Fariba Khodagholi

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, and Drug Design & Development Research Center, Tehran University of Medical Sciences, 14176, Tehran, Iran

    Niloufar Ansari & Mohsen Amini

  3. Department of Medicinal Chemistry, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 14176, Tehran, Iran

    Abbas Shafiee

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  1. Solaleh Khoramian Tusi
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Correspondence to Fariba Khodagholi.

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Tusi, S.K., Ansari, N., Amini, M. et al. Attenuation of NF-κB and activation of Nrf2 signaling by 1,2,4-triazine derivatives, protects neuron-like PC12 cells against apoptosis. Apoptosis 15, 738–751 (2010). https://doi.org/10.1007/s10495-010-0496-6

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