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A Novel Compound ITC-3 Activates the Nrf2 Signaling and Provides Neuroprotection in Parkinson’s Disease Models

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder accompanied by a selective loss of the dopamine(DA)ergic neurons residing in the substantia nigra. There is ample evidence that neuroinflammation and oxidative stress are involved in the pathogenesis of PD. In the present study, we aimed at protecting the DAergic neurons by suppressing these cellular events and generated a novel synthetic isothiocyanate ITC-3. The compound led to elevation of nuclear and total levels of the transcription factor Nrf2 and interacted with its binding protein Keap1 with high affinity, suggesting Nrf2 activation. ITC-3 was able to suppress production of the proinflammatory mediators in lipopolysaccharide-activated BV-2 microglial cells. It also increased mRNA and protein levels of the Nrf2-dependent antioxidant enzymes NAD(P)H quinone oxidoreductase, heme oxygenase-1, and glutamylcysteine ligase in both BV-2 and DAergic neuronal CATH.a cells. The compound protected the DAergic cells against oxidative stress. In vivo, ITC-3 attenuated the loss of tyrosine hydroxylase-immunopositive nigrostriatal DAergic neurons, suppressed microglial activation, and abolished PD-associated motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-elicited animal model of PD. Taken together, ITC-3 may be useful toward development of neuroprotective therapy for PD.

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Abbreviations

BH4:

Tetrahydrobiopterin

BSA:

Bovine serum albumin

DA:

Dopamine

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine serum

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GCLC:

Glutamate-cysteine ligase catalytic subunit

GCLM:

Glutamate-cysteine ligase modulatory subunit

HO-1:

Heme oxygenase-1

IL-1β:

Interleukin-1β

iNOS:

Inducible nitric oxide synthase

LDH:

Lactate dehydrogenase

LPS:

Lipopolysaccharide

MPP+ :

1-methyl-4-phenylpyridinium

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Nrf2:

Nf-E2-related factor 2

NQO1:

NAD(P)H quinone oxidoreductase

NO:

Nitric oxide

PD:

Parkinson’s disease

PMSF:

Phenylmethylsulfonyl fluoride

ROS:

Reactive oxygen species

RT-PCR:

Reverse transcription-polymerase chain reaction

SN:

Substantia nigra

SPR:

Surface plasmon resonance

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

JA Lee and HJ Son made equal contributions. We thank Dr. Ghilsoo Nam for her participation in the synthesis of ITC-3. This study was supported by the National Agenda Project from Korea Research Council of Fundamental Science and Technology (OH) and in part by the National Research Foundation of Korea (NRF-2009-0081674, DJK; NRF-2009-0081675, OH).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea

    Ji Ae Lee, Hyo Jin Son, Se Hee Han, Nari Shin, Ji Hyun Kim, Hye Ri Kim & Onyou Hwang

  2. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 136-791, South Korea

    Ki Duk Park & Dong Jin Kim

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  1. Ji Ae Lee
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  2. Hyo Jin Son
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Correspondence to Onyou Hwang.

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Lee, J.A., Son, H.J., Park, K.D. et al. A Novel Compound ITC-3 Activates the Nrf2 Signaling and Provides Neuroprotection in Parkinson’s Disease Models. Neurotox Res 28, 332–345 (2015). https://doi.org/10.1007/s12640-015-9550-z

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