Research Paper Advance Articles

Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson’s disease models through activating the MEF2-PGC1α and BDNF/CREB pathways

Haiyun Chen1,2, *, , Jie Cao1, *, , Ling Zha1, , Peile Wang1, , Zheng Liu1,3, , Baojian Guo1, , Gaoxiao Zhang1, , Yewei Sun1, , Zaijun Zhang1, , Yuqiang Wang1, ,

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization, Innovative Drug Development of Chinese Ministry of Education, Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, China
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
  • 3 Foshan Stomatology Hospital, School of Stomatology and Medicine, Foshan University, Foshan, China
* Equal contribution

Received: March 11, 2020       Accepted: June 4, 2020       Published: July 24, 2020      

https://doi.org/10.18632/aging.103551
How to Cite

Copyright © 2020 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

T-006, a new derivative of tetramethylpyrazine, has been recently found to protect against 6-hydroxydopamine (6-OHDA)-induced neuronal damage and clear α-synuclein (α-syn) by enhancing proteasome activity in an α-syn transgenic Parkinson’s disease (PD) model. The effect of T-006 on the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model, however, has not been tested and T-006’s neuroprotective mechanisms have not been fully elucidated. In this study, we further investigated the neuroprotective and neurogenic effects of T-006 and explored its underlying mechanism of action in both cellular and animal PD models. T-006 was able to improve locomotor behavior, increase survival of nigra dopaminergic neurons and boost striatal dopamine levels in both MPTP- and 6-OHDA-induced animals. T-006 treatment restored the altered expressions of myocyte enhancer factor 2D (MEF2D), peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC1α) and NF-E2-related factor 1/2 (Nrf1/2) via modulation of Akt/GSK3β signaling. T-006 stimulated MEF2, PGC1α and Nrf2 transcriptional activities, inducing Nrf2 nuclear localization. Interestingly, T-006 promoted endogenous adult neurogenesis toward a dopaminergic phenotype by activating brain-derived neurotrophic factor (BDNF) and cAMP responsive element-binding protein (CREB) in 6-OHDA rats. Our work demonstrated that T-006 is a potent neuroprotective and neuroregenerative agent that may have therapeutic potential in the treatment of PD.

Abbreviations

PD: Parkinson’s disease; 6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+: 1-methyl-4-phenylpyridinium; MEF2D: myocyte enhancer factor 2D; PGC1α: peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α; Nrf1/2: NF-E2-related factor 1/2; ARE: antioxidant response element; BDNF: brain-derived neurotrophic factor; CREB: cAMP responsive element-binding protein; DA: dopaminergic; NSCs: neural stem cells; NPCs: neural progenitor cells; SVZ: subventricular zone; LV: lateral ventricles; DG: dentate gyrus; TMP: tetramethylpyrazine; BrdU: 50-bromo-20-deoxyuridine; APO: apomorphine; TH: tyrosine hydroxylase; DCX: doublecortin; p-GSK3β: phospho-Ser9-GSK3β; DOPAC: 3, 4-dihydroxyphenylacetic acid; HVA: homovanilic acid; p-MEF2D: phospho-Ser444-MEF2D; p-Akt: phospho-Ser473-Akt; CGNs: cerebellar granule neurons; hiPSCs: human induced pluripotent stem cells; MTT: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide.