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A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappa B and the PKC alpha/PI3-K/Akt pathways
Xu, Da-Ping1,2; Zhang, Kun3; Zhang, Zai-Jun1,2,3; Sun, Ye-Wei3; Guo, Bao-Jian3; Wang, Yu-Qiang3; Hoi, Pui-Man3; Han, Yi-Fan2; Lee, Simon Ming-Yuen1
2014
Source PublicationNEUROCHEMISTRY INTERNATIONAL
ISSN0197-0186
Volume78Pages:76-85
Abstract

Introduction

The natural product tetramethylpyrazine (TMP) has a variety of biologic activities, including neuroprotection. Nitrones are powerful free radical scavengers. We have designed and synthesized a TMP derivative, TN-2, which is armed with two nitrone moieties.

Aims

In this study, we investigated the neuroprotective effect of TN-2 against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro and in zebrafish.

Methods

PC12 cells, zebrafish and rats were exposed to 6-OHDA challenge. MTT assay, LDH release, Hoechst staining, DAF-FM staining, luciferase reporter construct transfection, and western blotting were applied to detect cell viability, apoptosis, intracellular nitric oxide (NO), NF-κB transcriptional activity and proteins expression. In zebrafish, whole-mount staining and real-time PCR were performed to quantify dopaminergic neurons and mRNA expression. Hematoxylin and eosin staining and immunohistochemistry for glial fibrillary acidic protein were used to detect the astrocyte activation in the unilateral 6-OHDA rat model.

Results

TN-2 but not TMP exhibited potent neuroprotective effect against 6-OHDA-induced apoptosis in PC12 cells. Moreover, TN-2 prevented dopaminergic neuron loss and suppressed mRNA expression of pro-inflammatory genes, including IL-1β, TNF-α and COX-2, in 6-OHDA-treated zebrafish. TN-2 remarkably attenuated microglial/astrocyte activation in the unilateral 6-OHDA rat model. The mechanistic study demonstrated that TN-2 inhibited over-production of intracellular NO and protein expression of inducible nitric oxide synthase through down-regulating NF-κB activity. Additionally, the PKCα/PI3-K/Akt pathway was also involved in the neuroprotection of TN-2.

Conclusion

These results suggest that TN-2 protected against 6-OHDA-induced neurotoxicity via modulating the NF-κB-medicated neuroinflammation and PKCα/PI3-K/Akt pathways.

KeywordNeuroinflammation Tetramethylpyrazine Derivative 6-hydroxydopamine Neuroprotection
DOIhttps://doi.org/10.1016/j.neuint.2014.09.001
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Neurosciences & Neurology
WOS SubjectBiochemistry & Molecular Biology ; Neurosciences
WOS IDWOS:000347501400010
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Cited Times [WOS]:13   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Macao, China
2.Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China
3.Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou 510632, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Xu, Da-Ping,Zhang, Kun,Zhang, Zai-Jun,et al. A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappa B and the PKC alpha/PI3-K/Akt pathways[J]. NEUROCHEMISTRY INTERNATIONAL,2014,78:76-85.
APA Xu, Da-Ping.,Zhang, Kun.,Zhang, Zai-Jun.,Sun, Ye-Wei.,Guo, Bao-Jian.,...&Lee, Simon Ming-Yuen.(2014).A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappa B and the PKC alpha/PI3-K/Akt pathways.NEUROCHEMISTRY INTERNATIONAL,78,76-85.
MLA Xu, Da-Ping,et al."A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappa B and the PKC alpha/PI3-K/Akt pathways".NEUROCHEMISTRY INTERNATIONAL 78(2014):76-85.
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