Research Paper Volume 12, Issue 14 pp 14897—14917
Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson’s disease models through activating the MEF2-PGC1α and BDNF/CREB pathways
- 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
Received: March 11, 2020 Accepted: June 4, 2020 Published: July 24, 2020
https://doi.org/10.18632/aging.103551How to Cite
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.