Tetramethylpyrazine nitrone exerts neuroprotection via activation of PGC-1α/Nrf2 pathway in Parkinson's disease models

Baojian Guo; Chengyou Zheng; Jie Cao; Fangcheng Luo; Haitao Li; Shengquan Hu; Simon Mingyuan Lee; Xifei Yang; Gaoxiao Zhang; Zaijun Zhang; Yewei Sun; Yuqiang Wang

doi:10.1016/j.jare.2023.11.021

Tetramethylpyrazine nitrone exerts neuroprotection via activation of PGC-1α/Nrf2 pathway in Parkinson's disease models

J Adv Res. 2023 Nov 19:S2090-1232(23)00360-0. doi: 10.1016/j.jare.2023.11.021. Online ahead of print.

Authors

Baojian Guo¹, Chengyou Zheng², Jie Cao³, Fangcheng Luo³, Haitao Li⁴, Shengquan Hu⁵, Simon Mingyuan Lee⁶, Xifei Yang⁷, Gaoxiao Zhang³, Zaijun Zhang⁸, Yewei Sun⁹, Yuqiang Wang³

Affiliations

¹ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, and Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
² State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, and Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China; School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China.
³ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, and Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China.
⁴ Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China.
⁵ Shenzhen Institute of Translational Medicine/Shenzhen Institute of Gerontology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China.
⁶ Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao.
⁷ Key Laboratory of Modern Toxicology of Shenzhen, Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen 518055, China.
⁸ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, and Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China. Electronic address: zaijunzhang@163.com.
⁹ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, and Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China. Electronic address: yxy0723@163.com.

PMID: 37989471
DOI: 10.1016/j.jare.2023.11.021

Abstract

Introduction: Parkinson's disease (PD) is common neurodegenerative disease where oxidative stress and mitochondrial dysfunction play important roles in its progression. Tetramethylpyrazine nitrone (TBN), a potent free radical scavenger, has shown protective effects in various neurological conditions. However, the neuroprotective mechanisms of TBN in PD models remain unclear.

Objectives: We aimed to investigate TBN's neuroprotective effects and mechanisms in PD models.

Methods: TBN's neuroprotection was initially measured in MPP⁺/MPTP-induced PD models. Subsequently, a luciferase reporter assay was used to detect peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) promoter activity. Effects of TBN on antioxidant damage and the PGC-1α/Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway were thoroughly investigated.

Results: In MPP⁺-induced cell model, TBN (30-300 μM) increased cell survival by 9.95 % (P < 0.05), 16.63 % (P < 0.001), and 24.09 % (P < 0.001), respectively. TBN enhanced oxidative phosphorylation (P < 0.05) and restored PGC-1α transcriptional activity suppressed by MPP⁺ (84.30 % vs 59.03 %, P < 0.01). In MPTP-treated mice, TBN (30 mg/kg) ameliorated motor impairment, increased striatal dopamine levels (16.75 %, P < 0.001), dopaminergic neurons survival (27.12 %, P < 0.001), and tyrosine hydroxylase expression (28.07 %, P < 0.01). Selegiline, a positive control, increased dopamine levels (15.35 %, P < 0.001) and dopaminergic neurons survival (25.34 %, P < 0.001). Additionally, TBN reduced oxidative products and activated the PGC-1α/Nrf2 pathway. PGC-1α knockdown diminished TBN's neuroprotective effects, decreasing cell viability from 73.65 % to 56.87 % (P < 0.001).

Conclusion: TBN has demonstrated consistent effectiveness in MPP⁺-induced midbrain neurons and MPTP-induced mice. Notably, the therapeutic effect of TBN in mitigating motor deficits and neurodegeneration is superior to selegiline. The neuroprotective mechanisms of TBN are associated with activation of the PGC-1α/Nrf2 pathway, thereby reducing oxidative stress and maintaining mitochondrial function. These findings suggest that TBN may be a promising therapeutic candidate for PD, warranting further development and investigation.

Keywords: Nuclear factor erythroid-2-related factor 2; Parkinson’s disease; Peroxisome proliferator-activated receptor γ co-activator 1α; Tetramethylpyrazine nitrone.